COMT inhibitors for the treatment of depression and impaired cognition

ABSTRACT

The present invention relates to compounds of formula I 
                         
wherein R 1  is as defined in the specification
 
and to esters thereof which are hydrolyzable under physiological conditions and to the pharmaceutically acceptable salts thereof. The compounds of the invention are inhibitors of COMT and, thus, are useful for the treatment of diseases for which COMT inhibition is beneficial. The invention further relates to the treatment, control, or prevention of diseases such as depression, schizophrenia, Parkinson&#39;s disease, and to improve cognition.

FIELD OF THE INVENTION

The present invention relates to compounds that inhibitcatechol-O-methyltransferase (COMT) and their use for improvingcognitions and in the treatment of CNS disorders such as depression,schizophrenia, and Parkinson's disease.

BACKGROUND OF THE INVENTION

Numerous documents describe the current knowledge on COMT—inhibition,for example—in the field of depression:

-   Fava, M., J. F. Rosenbaum, A. R. Kolsky, J. E. Alpert, A. A.    Nierenberg, M. Spillmann, C. Moore, P. Renshaw, T. Bottiglieri, G.    Moroz, and G. Magni. Open study of the catechol-O-methyltransferase    inhibitor tolcapone in major depressive disorder. J Clin.    Psychopharmacol. 1999, 19, 329.

—in the Field of Schizophrenia:

-   Weickert, C. S., and D. R. Weinberger. A candidate molecule approach    to defining developmental pathology in schizophrenia. Schizophr Bull    1998, 24, 303.-   Weinberger, D. R., M. F. Egan, A. Bertolino, J. H. Callicott, V. S.    Mattay, B. K. Lipska, K. F. Berman, and T. E. Goldberg. Prefrontal    neurons and the genetics of schizophrenia. Biol Psychiatry 2001, 50,    825.-   Egan, M. F., T. E. Goldberg, B. S. Kolachana, J. H. Callicott, C. M.    Mazzanti, R. E. Straub, D. Goldman, and D. R. Weinberger. Effect of    COMT Val108/158 Met genotype on frontal lobe function and risk for    schizophrenia. Proc. Natl. Acad. Sci. U S A 2001, 98, 6917

—in the Field of Parkinson's Disease

-   Two COMT inhibitors are marketed for improvement of levodopa    therapy, Tasmar/Tolcapone-   M. C. Kurth, C. H. Adler, M. St. Hilaire, C. Singer, C. Waters, P.    LeWitt, D. A. Chernik, E. E. Dorflinger, K. Yoo,; Tolcapone improves    motor function and reduces levodopa requirement in patients with    Parkinson's disease experiencing motor fluctuations: A multicenter,    double-blind, randomized, placebo-controlled trial. Neurology, 1997,    48, 81-87;-   V. V. Myllylä, M. Jackson, J. P. Larsen, H. Baas, Eur. J Neurol.,    1997, 4, 333-341);-   Pfeiffer, Ronald F Catechol-O-methyltransferase in Parkinson's    disease. Neurological Disease and Therapy (2003), 59(Handbook of    Parkinson's Disease (3rd Edition)), 437-451; and Entacapone    Gershanik, Oscar; Emre, Murat; Bernhard, Gudrun; Sauer, Dirk.    Efficacy and safety of levodopa with entacapone in Parkinson's    disease patients suboptimally controlled with levodopa alone, in    daily clinical practice: an international, multicentre, open-label    study. Progress in Neuro-Psychopharmacology & Biological Psychiatry    2003, 27(6), 963-971.

—in the Field of Cognition Improvement

-   Lachman, H. M., D. F. Papolos, T. Saito, Y. M. Yu, C. L. Szumlanski,    and R. M. Weinshilboum. Human catechol-O-methyltransferase    pharmacogenetics: description of a functional polymorphism and its    potential application to neuropsychiatric disorders.    Pharmacogenetics 1996, 6, 243.-   Malhotra, A. K., L. J. Kestler, C. Mazzanti, J. A. Bates, T.    Goldberg, and D. Goldman. A functional polymorphism in the COMT gene    and performance on a test of prefrontal cognition. Am J Psychiatry    2002, 159, 652.

SUMMARY OF THE INVENTION

The invention provides purine derivatives of formula

wherein

-   -   R¹ is H, CN, halogen, —COR², —S(O),R², C₁₋₁₂-alkyl,        C₂₋₁₂-alkenyl, C₃₋₈-cycloalkyl, a heterocyclyl group, an aryl        group, a heteroaryl group, C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, a        heterocyclyl-(C₁₋₃)-alkyl group, an aryl-(C₁₋₃)-alkyl group, or        a heteroaryl-(C₁₋₃)-alkyl group; wherein the alkyl, alkenyl,        alkoxy, cycloalkyl, heterocyclyl group, aryl group and        heteroaryl groups are optionally substituted;    -   R² is —N(R³)(R^(3′)), C₁₋₆-alkyl, C₃₋₈-cycloalkyl, heterocyclyl,        aryl, heteroaryl, C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, a        heterocyclyl-(C₁₋₃)-alkyl group, an aryl-(C₁₋₃)-alkyl group, or        a heteroaryl-(C₁₋₃)-alkyl group, wherein the C₁₋₆-alkyl,        C₃₋₈-cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally        substituted;    -   R³ and R^(3′) are independently hydrogen or (C₁₋₃)-alkyl;    -   x is 0, 1 or 2;        and to an ester thereof which is hydrolyzable under        physiological conditions and to a pharmaceutically acceptable        salt thereof.

The invention also provides processes for the manufacture of compoundsof the invention and their pharmaceutically acceptable salts. Theinvention further provides pharmaceutical compositions containing aneffective amount of one or more compounds of formula I per se, orpharmaceutically acceptable salts thereof, and a pharmaceuticallyacceptable carrier and methods for the manufacture of such compositions.

The compounds of the invention possess valuable pharmacologicalproperties. In particular, these compounds inhibit the enzymecatechol-O-methyltransferase (COMT), a magnesium-dependent enzyme whichcatalyzes the transfer of the methyl group of S-adenosylmethionine to acatechol substrate, whereby the corresponding methyl ethers are formed.Suitable substrates which can be O-methylated by COMT and which can thusbe deactivated are, for example, extraneuronal catecholamines andexogeneously-administered therapeutically active substances having acatechol structure.

The invention also provides methods for the treatment, prevention, orcontrol of illnesses in which a deactivation of extraneuronalcatecholamines by COMT plays a role, for example, in the prevention orcontrol of depressions. In this case the compounds of the invention canbe used as individual compounds or in combination with othertherapeutically active substances which favorably influence the courseof the illness. The compounds of the invention can, however, also beused as co-medications with other therapeutically active substances. Inaddition the compounds of the invention are COMT inhibitors that lackthe potential toxicity associated with nitrocatechol containingcompounds (K. S. Smith, P. L. Smith, T. N. Heady, J. M. Trugman, W. D.Harman, T. L. Macdonald, Chem. Res. Toxicol. 2003, 16, 123-128; M.d'Ischia, C. Costantini, Bioorganic & Medicinal Chemistry 1995, 3,923-927).

The compounds of the invention can also be used for the control ofillnesses with therapeutically active substances which have a catecholstructure. The treatment of Parkinson's disease and of parkinsonism withL-dopa, a therapeutically active substance having the catecholstructure, can be mentioned as an example. In such cases the compoundsof formula I can be used in the form of a co-medication or ascombination preparations. The compounds of the invention can also beused for the treatment of schizophrenia and to improve cognition.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the terms used in the present descriptionshall apply irrespective whether these terms are used alone or incombination. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an,” and “the” include pluralforms unless the context clearly dictates otherwise.

The term “alkyl” denotes a straight or branched chain hydrocarbon group.The number of carbon atoms in a given alkyl group is indicated by thenumbers listed, for example “C₁₋₁₂-alkyl” indicates an alkyl group with1 to 12 carbon atoms. Preferred alkyl groups are those with 1 to 6carbon atoms. Examples of such groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl,neopentyl, tert.-pentyl, hexyl, isohexyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. The alkyl groupsmay optionally be substituted by halogen, hydroxy, or alkoxy, especiallyby halogen. Examples of such substituted alkyl groups are, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl,hydroxymethyl, methoxymethyl, 2-methoxyethyl, and the like.

The term “alkoxy” represent an alkyl-O-group, where the alkyl part is asdefined above.

The term “cycloalkyl” represents a saturated cyclic hydrocarbon,preferably a saturated cyclic hydrocarbon having from 3 to 8 carbonatoms, “C₃₋₈cycloalkyl.” Such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; thecycloalkyl group may optionally be substituted by an alkyl group asdefined above. Examples of such substituted groups aremethylcyclopropyl, ethylcyclopropyl, methylcyclobutyl,methylcyclopentyl, methyl-2-cyclopentenyl, methyl-3-cyclopentenyl ormethylcyclohexyl.

The term “alkenyl” represents an unsaturated straight- or branched alkylchain having one or more double bonds. The term “C₂₋₁₂-alkenyl”represents an alkenyl group containing from 2 to 12 carbon atoms, forexample, ethylene, propylene, isopropylene, and the like.

The term “heterocyclyl” represents 3- to 7-membered non-aromaticheterocyclic group containing 1 or 2 hetero atoms selected fromnitrogen, oxygen and sulfur or sulfur oxidized to sulfones orsulfoxides. Examples of such groups are oxiranyl, azetidinyl, oxetanyl,thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl.Preferred heterocycles are piperidyl and morpholinyl. Such heterocyclicgroups may optionally be substituted by alkyl or alkoxy.

The term “aryl” represents an mono- or bicyclic aromatic hydrocarbongroup having 6 to 10 carbon atoms, examples of such groups are phenyl ornaphthyl, a preferred aryl group is phenyl. These aryl groups mayoptionally be further substituted by one or several substituents chosenfrom halogen, alkyl or alkoxy groups as defined above. Examples of suchsubstituted aryl groups are, 2,3 or 4-fluorophenyl, 2,3 or4-bromophenyl, 2,3 or 4-chlorophenyl, 2,3 or 4-methylphenyl, 2,6- or3,5-difluorophenyl, 2,6- or 3,5-dichlorophenyl, 2,6- or3,5-dibromophenyl or 2,6- or 3,5-dimethylphenyl, and the like.

The term “heteroaryl group” represents an aromatic mono- or bicyclicgroup, wherein each ring contains 5 or 6 members, having 1 to 4heteroatoms chosen from N, O and S. Examples of such monocyclic aromaticheterocyclic groups include pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl,furanyl, thiophenyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, 1,2,3-triazolyland tetrazolyl; examples of bicyclic heteroaryl groups are benzofuranyl,isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzodioxolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl or phthalazinyl. The“heteroaryl groups” may be further substituted by halogen or an alkylgroup as defined above.

“Halogen” stands for fluorine, chlorine, bromine or iodine.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc. means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, which are generally safe, non-toxic, andneither biologically nor otherwise undesirable, and that possess thedesired pharmacological activity of the parent compound. These salts arederived from an inorganic or organic acid or base.

“Pharmaceutically acceptable adjuvant” means a subsidiary ingredient oradditive in a mixture of a composition which contributes to theeffectiveness of the primary ingredient, such as solubilizers,stabilizing agents, wetting agents, emulsifying agents, flavor-improvingagents such as sweetening agents and flavoring agents, coloring agents,salts for varying the osmotic pressure, buffers, coating agents andantioxidants.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

The invention provides purine derivatives of formula

wherein

-   -   R¹ is H, CN, halogen, —COR², —S(O)_(x)R², C₁₋₁₂-alkyl,        C₂₋₁₂-alkenyl, C₃₋₈-cycloalkyl, a heterocyclyl group, an aryl        group, a heteroaryl group, C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, a        heterocyclyl-(C₁₋₃)-alkyl group, an aryl-(C₁₋₃)-alkyl or a        heteroaryl-(C₁₋₃)-alkyl group; wherein the alkyl, alkenyl,        alkoxy, cycloalkyl, heterocyclyl group, aryl and heteroaryl        groups are optionally substituted;    -   R² is —N(R³)(R^(3′)), C₁₋₆-alkyl, C₃₋₈-cycloalkyl, heterocyclyl,        aryl, heteroaryl, C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, a        heterocyclyl-(C₁₋₃)-alkyl group, an aryl-(C₁₋₃)-alkyl group, or        a heteroaryl-(C₁₋₃)-alkyl group, wherein the C₁₋₆-alkyl,        C₃₋₈-cycloalkyl, heterocyclyl, aryl, and heteroaryl are        optionally substituted;    -   R³ and R^(3′) are independently hydrogen or (C₁₋₃)-alkyl;    -   x is 0, 1 or 2;        and to an ester thereof which is hydrolyzable under        physiological conditions and to a pharmaceutically acceptable        salt thereof.

Preferred compounds of formula I are compounds wherein R¹ is a hydrogen,cyano, halogen, —COR², —S(O)₂R², C₁₋₆-alkyl, C₁₋₆-alkyl substituted withhalogen, C₂₋₆-alkenyl substituted with COR², phenyl, phenyl substitutedwith C₁₋₆-alkyl or halogen, benzyl, benzyl substituted with C₁₋₆-alkyl,or heteroaryl. Noninclusive examples of heteroaryl groups are pyridinyl,thiazolyl or benzthiazolyl. Within this group of compounds are preferredcompounds wherein R² is C₁₋₆-alkyl, C₁₋₆-alkyl substituted with halogenor —N(R³)(R^(3′)) and wherein R³ and R^(3′) are independentlyC₁₋₃-alkyl. Another such group of preferred compounds are those whereinR² is phenyl, phenyl substituted with C₁₋₆-alkyl or halogen, cyclohexyl,or heteroaryl such as pyridinyl, thiazolyl or benzthiazolyl.

Preferred compounds are the compounds of formula I wherein R¹ ishydrogen, cyano, or halogen, such as for example

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-benzamide(Example 1);

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-cyano-2,3-dihydroxy-benzamide(Example 3);

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-bromo-2,3-dihydroxy-benzamide(Example 2); and

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-chloro-2,3-dihydroxy-benzamide(Example 7).

Further preferred compounds are the compounds of formula I wherein R¹ isC₁₋₆-alkyl, C₁₋₆-alkyl substituted with halogen, C₂₋₆-alkenylsubstituted with COR², wherein R² is —N(R³)(R^(3′)) and wherein R³ andR^(3′) are independently C₁₋₃-alkyl, such as for example

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-isopropyl-benzamide(Example 17);

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-(2-dihydroxy-carbamoyl-vinyl)-2,3-dihydroxy-benzamide(Example 15); and

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-trifluoromethyl-benzamide(Example 16).

A further group of preferred compounds are compounds of formula Iwherein R¹ is —COR². Within this group of compounds, preferred compoundsare those wherein R² is C₁₋₆-alkyl, C₁₋₆-alkyl substituted with halogen,—N(R³)(R^(3′)) and wherein R³ and R^(3′) are independently C₁₋₃-alkyl,such compounds are for example

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-trifluoroacetyl-benzamide(Example 4) and

N3-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-4,5-dihydroxy-N1,N1-dimethyl-isophthalamide(Example 14).

A further group of preferred compounds of formula I wherein R¹ is —COR²are those wherein R² is phenyl, phenyl substituted with C₁₋₆-alkyl orhalogen, C₃₋₈-cycloalkyl, or heteroaryl such as pyridinyl, thiazolyl orbenzthiazolyl, for example

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(4-methyl-benzoyl)-benzamide(Example 19);

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-cyclohexanecarbonyl-2,3-dihydroxy-benzamide(Example 6); and

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(pyridine-4-carbonyl)-benzamide(Example 5).

A further preferred group of compounds are the compounds of formula Iwherein R¹ is —S(O)₂R². Preferred compounds within this group ofcompounds are those wherein R² is C₁₋₆-alkyl, C₁₋₆-alkyl substitutedwith halogen, —N(R³)(R^(3′)) and wherein R³ and R^(3′) are independentlyC₁₋₃-alkyl. Also preferred within this group of compounds are thosewherein R² is phenyl, phenyl substituted with C₁₋₆-alkyl or halogen,cyclohexyl, or heteroaryl such as pyridinyl, thiazolyl or benzthiazolyl,for example

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(toluene-4-sulfonyl)-benzamide(Example 18).

A further preferred group of compounds are the compounds of formula Iwherein R¹ is phenyl, phenyl substituted with C₁₋₆-alkyl or halogen,pyridinyl, thiazolyl, benzthiazolyl, benzyl, or benzyl substituted withC₁₋₆-alkyl, such as for example

4′-Fluoro-4,5-dihydroxy-biphenyl-3-carboxylic acid{3-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-amide(Example 8);

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-thiazol-2-yl-benzamide(Example10);

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-pyridin-4-yl-benzamide(Example 12);

4,5-Dihydroxy-4′-methyl-biphenyl-3-carboxylic acid{3-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-amide(Example 9);

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-benzothiazol-2-yl-2,3-dihydroxy-benzamide(Example 11); and

N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(4-methyl-benzyl)-benzamide(Example 13).

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by methods known in the art, for example, byprocess described below, which process comprises

a) reacting9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3)di-oxol-4-yl}-9H-purin-6-amine of formula II

with an optionally protected 2,3-dihydroxy-benzoic acid derivativesubstituted by R¹ in position 5

wherein R¹ is as defined above in the presence of(3-dimethylamino-propyl)-ethyl-carbodiimide (EDC), triethyl amine andN-hydroxy-succinimide (HOSu) in a suitable solvent such asdichloroethylene andb) subsequent deprotection of the hydroxy groups where necessary withtrifluoroacetic acid in an aqueous solution to form the compounds offormula I.

The amino-purine derivative of formula II can be prepared according toScheme 1 starting from2-(6-Amino-purin-9-yl)-5-hydroxymethyl-tetrahydro-furan-3,4-diol (1)which is protected and subsequently reacted with(triphenyl-phosphanylidene)-acetic acid ethyl ester to the ester (4).The ester group in compound (4) is reduced to the alcohol (5) andtransformed into the amide of formula II

wherein TsOH stand for tosylchloride, IBX for1-hydroxy-1,2-benziodoxol-3(1H)-1-oxide, DMSO for dimethylsulfoxide,PPh₃ for triphenylphosphine, DEAD for diethyl azodicarboxylate and THFfor tetrahydrofurane, Angew. Chem. (2001) 113, 4164.

The optionally protected 2,3-dihydroxy-benzoic acid derivativessubstituted by R¹ in position 5 (IIIa and IIIb) are prepared accordingto reaction schemes 2 to 6.

A method for the preparation of compounds of formula IIIb, wherein R¹ ishydrogen or bromine is given in Scheme 2.

step a) esterification of 2,3-dihydroxy-benzoic acid (7) dissolved in asuitable solvent for example an alcohol such as methanol in the presenseof thionylchloride to form the ester (8);step b) protection of the ester (8) by ketalisation of the two hydroxygroups with a suitable ketone, e.g. with dichlorodiphenylmethane;step c) hydrolysation of the ester group in the presence of a strongbase such a LiOH.step d) 2,3-dihydroxy-benzoic acid is brominated in acetic acid and inthe following steps e) to g) the carboxylic group is esterified to formthe ester (11), the two hydroxy groups are protected to form the ketal(12) and the ester group is cleaved as described for steps a) to c).

The compounds of formula IIIb wherein R¹ is chlorine can be prepared asdepicted in Scheme 3.

step a) 2-hydroxy-3-methoxy-benzoic acid (13) is chlorinated for examplewith N-chlorosuccinimide in acetic acid to yield5-chloro-2-hydroxy-3-methoxy benzoic acid (14);step b) the methoxy group of compound (14) is reacted with hydrobromicacid in acetic acid to yield 5-chloro-2,3-dihydroxybenzoic acid (15);

-   -   5-chloro-2,3-dihydroxy benzoic acid is then transformed into the        protected compounds IIIb, wherein R¹ is chlorine by        esterification of the carboxylic group, ketalisation of the two        hydroxy groups and subsequent cleavage of the ester group        (steps c) to e)) as described above.

Scheme 4 describes the preparation of derivatives of formula IIIb,wherein R¹ is —COR² and R² is trifluoromethyl, cyclohexyl orpyridin-4-yl. The protected 5-bromo-benzoic acid derivative (thecompound of formula IIIb, wherein R¹ is bromine) is converted to itslithium salt. Lithium-halogen exchange and reaction withethyl-trifluoroacetate, cyclohexane carboxylic acid methoxymethylamide,or pyridine-4-carbaldehyde followed by oxidation with IBX yielded thecorresponding derivatives of formula IIIb.

In Scheme 5 the preparation of further derivatives of formula IIIbstarting from protected 5-bromo benzoic acid ester (12) is shown. Thenitrile is obtained by Pd catalysed cyanation. Arylsubstitutents wereintroduced using a Pd catalysed Suzuki-coupling with arylboronic acids.

In Scheme 6 the preparation of several derivatives of formula IIIbstarting from protected 5-bromo benzoic acid derivative (12) is shown.5-Bromo benzoic acid ester (12) is first converted to the dioxaborolane(18) which is subsequently reacted with benzylbromides, bromo aryl orbromo heteroaryl compounds in a palladium catalysed Suzuki reaction toyield the corresponding derivatives IIIb.

In analogy to schemes 2, 3, 4, 5 and 6, compounds of formula I may beprepared, wherein R¹ is other than those as described in the aboveschemes.

The various compounds which are used as starting materials are known orcan be prepared according to known methods.

As mentioned earlier, the compounds of formula I inhibit the enzymeCOMT. The inhibitory activity can be determined in vitro with COMTobtained from rat liver. Rat liver homogenate is incubated in thepresence of a suitable substrate as described by Zürcher et al. in J.Neurochem. 1982, 38, 191-195 and the COMT activity is measured.

The IC50 values (concentration of the inhibitor at which 50% activity ofthe enzyme is observed) were determined in a radiochemical assaydescribed by Zürcher et al. (see above) and are listed in Table 1.

IC₅₀ values were determined as follows: The inhibitors were dissolved inMe₂SO as 1.2 mM stock solution and further diluted with Me₂SO. Thereactions were performed in standard polypropylene vials. 25 μl of theinhibitor in varying concentrations from 10⁻⁴ to 10⁻⁹ mol L⁻¹ were mixedwith 215 μl freshly prepared buffer-substrate mixture consisting of 170μl potassium phosphate buffer (0.1 mol L⁻¹, pH 7.6), 10 μl MgCl₂, (0.1mol L⁻¹), 10 μl dithiothreitol (0.065 mol L⁻¹) and 25 μl of tissueextract. The enzyme preparations were preincubated for 15 min at 37° C.The reaction was started by adding 30 μl substrate (benzene-1,2-diol,0.025 mol L⁻¹), 10 μl [³H]SAM (5.5 mmol L⁻¹, specific activity: 13.36 Bqmol⁻¹ (3.61 Cimol⁻¹) and 20 μl deionized H₂O, reaching a final substrateconcentration of 2.5 mM and a final [¹H]/[³H]SAM concentration of 183μM. The reaction was stopped after incubating the vials in a water-bathat 37° C. for 15 min by addition of 200 μl HOAc (5.7%) containingguaiacol (0.1 g L⁻¹). The reaction vessels were transferred intopolyethylene scintillation vials and 3 ml of scintillation fluid (5 gbutyl-PBD, dissolved in 200 ml toluene, made up to 1 L with n-hexane)was added. The vials were capped and more than 98% [³H]guajacol formedwas extracted into the organic phase by vigorous shaking for 3 min.

The samples were counted in a Beckmann LS 6000 TA scintillation counter.

TABLE 1 Example IC50 [nM] comparativeN-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 9 exampletetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5- nitro-benzamide 1N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 2600tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy- benzamide 2N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 28tetrahydro-furan-2-yl]-allyl}-5-bromo-2,3- dihydroxy-benzamide 3N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 29tetrahydro-furan-2-yl]-allyl}-5-cyano-2,3- dihydroxy-benzamide 4N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 39tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5- trifluoroacetyl-benzamide5 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 42tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(pyridine-4-carbonyl)-benzamide 6N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 83tetrahydro-furan-2-yl]-allyl}-5-cyclohexanecarbonyl-2,3-dihydroxy-benzamide 7N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 44tetrahydro-furan-2-yl]-allyl}-5-chloro-2,3- dihydroxy-benzamide 84′-Fluoro-4,5-dihydroxy-biphenyl-3-carboxylic 21 acid{3-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-amide 94,5-Dihydroxy-4′-methyl-biphenyl-3-carboxylic 23 acid{3-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-amide 10N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 27tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5- thiazol-2-yl-benzamide 11N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 29tetrahydro-furan-2-yl]-allyl}-5-benzothiazol-2-yl-2,3-dihydroxy-benzamide 12N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 23tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5- pyridin-4-yl-benzamide 13N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 608tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(4-methyl-benzyl)-benzamide 14N3-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 2000tetrahydro-furan-2-yl]-allyl}-4,5-dihydroxy-N1,N1-dimethyl-isophthalamide 15N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 97tetrahydro-furan-2-yl]-allyl}-5-(2-dimethyl-carbamoyl-vinyl)-2,3-dihydroxy-benzamide 16N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 35tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5- trifluoromethyl-benzamide17 N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 1370tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5- isopropyl-benzamide 18N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 213tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(toluene-4-sulfonyl)-benzamide 19N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy- 34tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(4-methyl-benzoyl)-benzamide

The present invention also provides pharmaceutical compositionscontaining an effective amount of one or more compounds of the inventionor esters, ethers, or pharmaceutically acceptable salts thereof and apharmaceutically acceptable carrier.

Suitable pharmaceutically acceptable carriers include non-toxic,pharmaceutically inert, inorganic or organic carriers. Suitable carriersfor tablets, coated tablets, dragees and hard gelatin capsules are, forexample, lactose, maize starch or derivatives thereof, talc, stearicacid or its salts. Suitable carriers for soft gelatin capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols.Depending on the nature of the active substances no carriers are,however, required in the case of soft gelatin capsules. Suitable carriermaterials for the preparation of solutions and syrups are, for example,water, polyols, saccharose, invert sugar and glucose. Suitable carriermaterials for injection solutions are, for example, water, alcohols,polyols, glycerine and vegetable oils. Suitable carrier materials forsuppositories are, for example natural or hardened oils, waxes, fats andsemi-liquid or liquid polyols.

The pharmaceutical compositions of the invention also can containpharmaceutical adjuvants. As pharmaceutical adjuvants there come intoconsideration the usual preserving agents, solubilizers, stabilizingagents, wetting agents, emulsifying agents, flavor-improving agents suchas sweetening agents and flavoring agents, coloring agents, salts forvarying the osmotic pressure, buffers, coating agents and antioxidants.

The pharmaceutical compositions of the invention conveniently containabout 25 mg to about 300 mg, preferably about 50 mg to about 150 mg, ofa compound of the invention, for example, a compound of formula I or anester thereof which is hydrolyzable under physiological conditions or ofa pharmaceutically acceptable salt thereof.

The present invention also provides a process for the manufacture ofpharmaceutical compositions. Such process comprises bringing one or morecompounds of the invention and, if desired, one or more therapeuticallyvaluable substances into a galenical administration form with one ormore pharmaceutically acceptable carriers and, if desired, one or morepharmaceutical adjuvants.

Compounds of the invention inhibit the enzymecatechol-O-methyltransferase (COMT). Thus, the invention providesmethods for the treatment, prevention, or control of illnesses in whicha deactivation of extraneuronal catecholamines by COMT plays a role, forexample, in the prevention or control of depressions. In this case thecompounds of the invention can be used as individual compounds or incombination with other therapeutically active substances which favorablyinfluence the course of the illness. The compounds of the invention can,also be used as co-medications with other therapeutically activesubstances. In addition the compounds of the invention are COMTinhibitors that lack the potential toxicity associated withnitrocatechol containing compounds (K. S. Smith, P. L. Smith, T. N.Heady, J. M. Trugman, W. D. Harman, T. L. Macdonald, Chem. Res. Toxicol.2003, 16, 123-128; M. d'Ischia, C. Costantini, Bioorganic & MedicinalChemistry 1995, 3, 923-927).

The compounds of the invention can also be used for the control ofillnesses with therapeutically active substances which have a catecholstructure. The treatment of Parkinson's disease and of parkinsonism withL-dopa, a therapeutically active substance having the catecholstructure, can be mentioned as an example. In such cases the compoundsof formula I can be used in the form of a co-medication or ascombination preparations. The compounds of the invention can also beused for the treatment of schizophrenia and to improve cognition.

Therefore, the invention provides a method for the treatment ofdepression which comprises administering to an individual atherapeutically effective amount of a compound of the invention, forexample a compound of formula I. The invention also provides a methodfor the treatment of Parkinson's disease which comprises administeringto an individual a therapeutically effective amount of a compound of theinvention, for example a compound of formula I. The invention furtherprovides a method for the treatment of schizophrenia which comprisesadministering to an individual a therapeutically effective amount of acompound of the invention, for example a compound of formula I. Theinvention provides a method for improving cognition which comprisesadministering to an individual an effective amount of a compound of theinvention, for example a compound of formula I.

The compound and compositions of the invention can be administered in aconventional manner, for example, orally, rectally, or parenterally. Thepharmaceutical compositions of the invention can be administered orally,for example, in the form of tablets, coated tablets, dragees, hard andsoft gelatin capsules, solutions, emulsions, or suspensions. Thepharmaceutical compositions also can be administered rectally, forexample, in the form of suppositories or parenterally, for example, inthe form of injectable solutions.

The dosage at which compounds of the invention, or ester derivativesthereof and salts thereof can vary within wide limits depending on theillness to be treated, the age and the individual condition of thepatient and on the mode of administration and will, of course, be fittedto the individual requirements in each particular case. For example, inthe improvement of the treatment with or without L-dopa a daily dosageof 25 mg to about 1000 mg, especially about 100 mg to about 300 mg,comes into consideration. Depending on the dosage it is convenient toadminister the daily dosage in several dosage units.

The Examples which follow will further illustrate the invention andcontain detailed information concerning the preparation of compounds offormula I and the used starting materials.

Experimental

Materials and Methods

Solvents for extractions and chromatography were of technical grade andwere distilled prior to usage. Reactions were performed using solventsof p.a. grade purchased from Fluka or J. T Baker or solvents ofcomparable quality. THF (tetrahydrofuran) was distilled from sodiumbenzophenone ketyl and CH₂Cl₂ from CaH₂.

Thin layer chromatography was performed on aluminum-backed sheets coatedwith SiO₂ 60 F₂₅₄ from Macherey-Nagel using UV-light (254 nm) fordetection. Column chromatography was performed using Fluka SiO₂ 60,40-63 mesh, at r.t. (room temperature) and at a pressure of 1·10⁶ to4·10⁶ Pa (0.1-0.4 bar)

Analytical HPLC was performed on a Merck LiChrospher® 100 RP-18 (250×4mm, 5 μm, 100 Å) column, using a linear gradient of CH₃CN in H₂O with0.1% TFA (trifluoro acetic acid), 5→55% in 20 min, a flow of 1 mL/min,and UV-detection at 254 nm.

Preparative HPLC was performed on a Merck LiChrosorb® RP-18 (250×25 mm,7 μm) column, using a linear gradient of CH₃CN in H₂O with 0.1% TFA, aflow of 10 mL/min and UV-detection at 254 nm.

Melting points were determined on a Büchi-510 apparatus and areuncorrected. Infrared spectra were recorded on a Perkin-Elmer 1600-FTspectrometer.

NMR spectra (¹H and ¹³C) were recorded at r.t. on Varian-Mercury 300 orBruker AMX-500 instruments.

Mass Spectra were recorded by the MS service of the Labortorium fürOrganische Chemie at ETH Zürich using IonSpec Ultima (MALDI, with2,5-dihydroxybenzoic acid or 2,4,6-trihy-droxyacetophenone/diammoniumcitrate 2:1 as matrix) and VG-TRIBID (EI) spectrometers.

Elemental analyses were performed by the Mikrolabor of the Laboratoriumfür Organische Chemie at ETH Zürich.

General Procedures (GP)

General Procedure 1 (GP1) for the Synthesis of methyl2,3-dihydroxybenzoate Derivatives from the Corresponding2,3-dihydroxybenzoic acids

To a solution of the 2,3-dihydroxy-benzoic acid (1 eq.) in MeOH wasslowly added SOCl₂ (3 eq.) via a syringe and the reaction mixture wasthen refluxed overnight. After evaporation of the solvent under reducedpressure the grayish solid was redissolved in EtOAc and washed twicewith saturated K₂CO₃ solution, then saturated NaCl solution before beingdried over MgSO₄ and the solvent evaporated in vacuo. Drying under highvacuum yielded the product as a grayish solid.

General Procedure (GP2) for the Protection of Catechols asdiarylmethylketals

General Procedure 2.1 (GP2.1) Protection as diphenylmethylketal.

Method A. A suspension of the corresponding methyl 2,3-dihydroxybenzoate(1 eq.) in dichlorodiphenylmethane (1.5 eq.) was stirred at 160° C. for40 min. After cooling to 50° C., 30 mL MeOH was added to the viscousbrown oil leading to the formation of a precipitate. The precipitate wasfiltered, washed with MeOH (3×20 mL) and dried under high vacuum toyield the desired compound as a colorless solid.

Method B. A suspension of the corresponding methyl 2,3-dihydroxybenzoate(1 eq.) in 3.7 mL dichlorodiphenylmethane (1.5 eq.) was stirred at 160°C. for 40 min. After cooling, EtOAc was added to the viscous mixture andthe solution was washed with saturated NaCl solution, dried over MgSO₄and evaporated under reduced pressure. The crude product was purifiedusing flash chromatography (silica gel, hexane/Et₂O 10:1) to yield thedesired compound as a colorless solid.

General Procedure 2.2 (GP2.2) Protection as4,4′-dimethoxy-diphenylmethylketal.

4,4′-Dimethoxybenzophenone (1.5 eq.) and oxalyl chloride (8 eq.) werestirred at 60° C. for 30 min., then the temperature was raised to 1 10°C. to remove the excess oxalyl chloride and the corresponding methyl2,3-dihydroxy-benzoate (1 eq.) was added to the reaction mixture. Thedark red solution was stirred at 160° C. for 40 min. After cooling,EtOAc was added to the viscous mixture and the solution was washed withsaturated NaCl solution, dried over MgSO₄ and evaporated under reducedpressure. The crude product was purified using flash chromatography(silica gel, hexane/Et₂O 10:1 or hexane/EtOAc 20:1).

General Procedure 3 (GP3) for the Synthesis of Catechol Carboxylic Acidsfrom the Corresponding Ester Precursors

The biphasic mixture of a solution of the methyl catechol carboxylate (1eq.) in 5 mL THF and a solution of LiOH.H₂O (3 eq.) in 5 mL H₂O wasrefluxed for 3 h. After cooling to r.t. the reaction mixture wasacidified by addition of 4 mL 10% AcOH—solution and poured into aseparatory funnel containing 50 mL H₂O and 50 mL EtOAc. The layers wereseparated and the aqueous layer was extracted twice with 20 mL EtOAc.The pooled organic fractions were washed twice with saturatedNaCl-solution before being dried over MgSO₄ and evaporated in vacuo toyield the desired compound as a colorless solid.

General Procedure 4 (GP4) for the Synthesis of Functionalized CatecholCarboxylic Acids Starting from6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

Method A. To a suspension of6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (1 eq.) in 3 mLMeOH, LiOMe (2 eq.) was added leading to the formation of a clearsolution, which was stirred 20 min. at r.t. Following evaporation of thesolvent under reduced pressure, the resulting white foam was driedovernight under vacuum. The residue was then redissolved in 10 mL dryTHF and cooled to −78° C. To this solution t-BuLi (1.5M solution inpentane, 2.5 eq.) was added dropwise via a syringe and the resultingdark yellow solution was stirred 30 min. at −78° C. The desiredelectrophile was added to the reaction mixture and the stirringcontinued 30 min. at low temperature. The cooling bath was removed andthe reaction was stirred another 2 h at r.t., followed by acidificationwith 10% AcOH-solution and extraction with EtOAc (2×30 mL). The organicfractions were pooled, dried over MgSO₄ and the solvent evaporated invacuo. The crude product was purified using flash chromatography (silicagel, hexane/EtOAc/AcOH) to give the title compound as a yellowish tocolorless solid.

Method B. To a solution of6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (1 eq.) in 8 mLdry THF, LiH (2 eq.) was added. The reaction mixture was stirred 15 min.at r.t., then cooled to −78° C. To this solution t-BuLi (1.5M solutionin pentane, 2.5 eq.) was added dropwise via a syringe and the resultingyellow solution was stirred 30 min. at −78° C. The desired electrophilewas added to the reaction mixture and the stirring continued 30 min. atlow temperature. The cooling bath was removed and the reaction wasstirred another 2 h at r.t., followed by acidification with 10%AcOH-solution and extraction with EtOAc (2×30 mL). The organic fractionswere pooled, dried over MgSO₄ and the solvent evaporated in vacuo. Thecrude product was purified using flash chromatography (silica gel,hexane/EtOAc/AcOH) to give the desired compound as a colorless solid.

General Procedure 5 (GP5) for the Synthesis of Biaryl CatecholCarboxylic Esters via Suzuki Reaction Between methyl6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate and theCorresponding Aryl Boronic Acid

To a solution of methyl6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (1 eq.) andPd(PPh₃)₄ (0.05 eq.) in 10 mL toluene, a solution of the desired arylboronic acid (4 eq.) in 1.5 mL EtOH and a solution of K₂CO₃ (6 eq.) in 1mL H₂O were added. This mixture was refluxed 2 h-4 h. After cooling tor.t. the mixture was partitioned between EtOAc and H₂O. The organiclayer was washed twice with saturated NaCl solution, dried over MgSO₄and evaporated in vacuo. The crude product was further purified usingflash chromatography (silica gel, hexane/EtOAc 20:1→5:1) to yield thedesired compound as a colorless solid.

General Procedure 6 (GP6) for the Preparation of Biaryl CatecholCarboxylic Esters via One-Pot Arylboronate—Suzuki Biaryl Synthesis

To a solution of methyl6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (1 eq.) in 20 mL drytoluene, Pd(PPh₃)₄ (0.05 eq.), bis(pinacolato)diboron (1.3 eq.) and KOAc(1.5 eq.) were added and the mixture refluxed for 4 h. After cooling tor.t. the reaction mixture was filtered over Celite, which was washedwith an additional 30 mL of toluene. The combined toluene fractions wereconcentrated in vacuo to ca. 10-15 mL. To this yellowish solutionPd(PPh₃)₄ (0.05 eq.), 1.2 eq. of the desired arylbromide, e.g.2-bromo-1,3-benzothiazole and a solution of K₂CO₃ (5 eq.) in 3 mL H₂Owere added and the reaction was refluxed for 16 h. After cooling tor.t., the mixture was partitioned between H₂O and EtOAc and the organicfraction was washed twice with 20 mL saturated NaCl solution, beforebeing dried over MgSO₄ and evaporated under reduced pressure. The crudeproduct was further purified using flash column chromatography (silicagel, hexane/EtOAc 20:1→9:1) to yield the desired compound as a colorlesssolid.

General Procedure 7 (GP7) for the Amide Coupling of Catechol CarboxylicAcids and9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine

To a solution of the catechol carboxylic acid (1 eq.) in 5 mL CH₂Cl₂,EDC.HCl (1-(dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride)(1.5 eq.) and N-hydroxy-succinimide (1.3 eq.) were added and thesolution was stirred 2 h at r.t. After addition of9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[1,3]di-oxol-4-yl}-9H-purin-6-amine (0.7 eq.-1 eq.) and Et₃N (0.1 mL,0.68 mmol) stirring was continued another 3 h, then the solution waspoured into a separatory funnel containing CH₂Cl₂ and H₂O and the phaseswere separated. The aqueous phase was extracted with CH₂Cl₂ (3×15 mL),then the combined organic fractions were washed with saturated aqueousNaCl solution, dried over MgSO₄, and evaporated under reduced pressure.The crude product was purified by flash chromatography on silica gel(CH₂Cl₂→CH₂Cl₂/MeOH=20:1) to yield the desired compound as a colorlessfoam.

General Procedure 8 (GP8) for the Synthesis of Target Molecules byDeprotection of the Acetonide and the Diarylmethylketal ProtectingGroups

The protected precusor was treated with 3 mL of a mixture of TFA and H₂O(1:1) at r.t. for 20-60 min. The reaction mixture was then lyophilized.The crude product was redissolved in 3 mL DMSO and purified usingpreparative HPLC chromatography. The product fractions were subsequentlylyophilized to yield the desired compound as a fluffy solid.

EXAMPLE 1 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-2,3-dihydroxy-benzamidea) 2,2-Diphenyl-benzo[1,3]dioxole-4-carboxylic acid{3-[(3aR,4R,6R,6aR)-6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-Diphenyl-1,3-benzodioxole-4-carboxylic acid (150 mg, 0.471 mmol, 1eq.), EDC.HCl (136 mg, 0.71 mmol, 1.5 eq.), N-hydroxy-succinimide (65mg, 0.565 mmol, 1.2 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrfuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(150 mg, 0.451 mmol, 1 eq.) and Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 189 mg (67%). Colorless foam. Mp.: 105° C. [α]_(D) ²⁰: −14.3(c=1.0, MeOH). IR (KBr): 3424m; 3175m; 2987w; 1651s; 1532s; 1455s;1373m; 1246s; 1082s; 867m; 748m. ¹H-NMR (300 MHz, CDCl₃): 1.37 (s, 3 H,CH_(3-exo)); 1.62 (s, 3 H, CH_(3-endo)); 4.05 (m, 2 H, H—C(7′),H—C(7″)); 4.69 (m, 1 H, H—C(4′)); 4.95 (dd; J=6.5, 3.7, 1 H, H—C(3′));5.46 (dd, J=6.5, 2.2, 1 H, H—C(2′)); 5.61 (bs, 2 H, NH₂); 5.86 (m, 2 H,H—C(5′), H—C(6′)); 6.08 (d, J=2.2, 1 H, H—C(1′)); 6.95 (t, J=8.1, 1 H,H_(arom, Cat.)); 7.02 (dd, J=8.1, 1.2, 1 H, H_(arom, Cat.)); 7.14 (t,J=5.6, 1 H, NHCO); 7.35-7.39 (m, 6 H, H_(arom, Ketal)), 7.48-7.53 (m, 4H, H_(arom, Ketal)); 7.58 (dd, J=8.7, 1.2, H_(arom, Cat.)); 7.84 (s, 1H, H—C(8)); 8.20 (s, 1 H, H—C(2)). ¹³C-NMR (75 MHz, CDCl₃): 25.5; 27.2;40.7; 84.0; 84.5; 87.1; 90.2; 111.8; 114.6; 115.5; 118.1; 120.1; 122.0;122.4; 126.3; 128.2; 128.3; 129.5; 130.6; 138.8; 139.6; 144.5; 147.0;149.3; 153.0; 155.3; 163.2. HR-MS (MALDI): calcd. for C₃₅H₃₃N₆O₆([M+H]⁺): 633.2461, found 633.2442.

b)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-2,3-dihydroxy-benzamide

The protected precursor (120 mg, 0.19 mmol) was treated with 3.5 mL of amixture of TFA and H₂O (5:2) at 0° C. for 60 min. The solvents wereevaporated under reduced pressure, then the residue was dissolved in 5%NH₄OH in H₂O and extracted with CHCl₃ (3×15 mL). The aqueous phase wasthen evaporated under reduced pressure and coevaporated with H₂O (3×10mL). The crude product was redissolved in 8 mL DMF and purified usingHPLC chromatography to yield the title compound as a colorless solid.

Yield: 60 mg (74%). Mp.: 134° C. (dec.). t_(R, analyt.): 10.9 min. IR(KBr): 3424 br, s; 1641s; 1604s; 1460w; 1420w; 1340w; 1278m; 1129w;1050w. ¹H-NMR (500 MHz, (CD₃)₂SO): 3.95 (m, 2 H, H—C(7′), H—C(7″)); 4.11(t, J=4.8, 1 H, H—C(4′)); 4.37 (m; 1 H, H—C(3′)); 4.65 (t, J=H,H—C(2′)); 5.82-5.93 (m, 2 H—C(5′), H—C(6′)); 5.93 (d, J=5.1, 1 H,H—C(1′)); 6.69 (t, J=7.9, 1 H, H_(arom, Cat.)); 6.92 (dd, J=7.9, 1.1, 1H, H_(arom, Cat.)); 7.31 (dd, J=7.9, 1 H, H_(arom, Cat.)); 8.23 (s, 1 H,H—C(8)); 8.49 (s, 1 H, H—C(2)); 8.97 (t, J=5.4, 1 H, H—NHCO); 12.64 (bs,1 H, OH). ¹³C-NMR (125 MHz, (CD₃)₂SO): 40.1; 73.1; 73.9; 84.3; 87.8;115.0; 117.2; 118.0; 118.9; 119.1; 129.2; 129.6; 141.3; 146.2; 148.9;149.0; 149.6; 153.2; 169.5. HR-MS (MALDI): calcd. for C₁₉H₂₁N₆O₆([M+H]⁺): 429.1522, found 429.1513.

EXAMPLE 2 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-bromo-2,3-dihydroxy-benzamidea) Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

Methyl 5-bromo-2,3-dihydroxybenzoate (3 g, 12.87 mmol, 1 eq.) wasreacted with dichlorodiphenylmethane (3.7 mL, 4.58 g, 19.31 mmol, 1.5eq.) according to GP2, Method A.

Yield: 4 g (76%). Colorless powder. Mp.: 146-148° C. IR (KBr): 3079w;2950w; 1718s (CO); 1467s; 1355s; 1238s; 1204s; 1043s; 1013s; 944m; 867m;780s. ¹H-NMR (300 MHz, CDCl₃): 3.94 (s, 3 H, CH₃); 7.14 (d, J=1.9, 1 H,H_(arom, Cat.)); 7.38-7.41 (m, 6 H, H_(arom, Ketal)); 7.55-7.59 (m, 5 H,H_(arom, Cat.), H_(arom, Ketal)). ¹³C-NMR (75 MHz, CDCl₃): 52.4; 112.6;113.7; 115.6; 119.1; 125.0; 126.2; 128.3; 129.4; 139.0; 147.5; 149.1;163.7. HR-MS (MALDI): calcd. for C₂₁H₁₆BrO₄ ([M+H]⁺): 411.0231, found411.0220.

b) 6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (0.5 g, 1.216mmol, 1 eq.) and LiOH.H₂O (204 mg, 4.86 mmol, 4 eq.) were reactedaccording to GP3.

Yield: 437 mg (91%). Colorless solid. Mp.: 215° C. IR (KBr): 3063m; 2873br, m; 2538m; 1695s (CO); 1598w; 1468s; 1406m; 1350m; 1287s; 1234s;1202s; 1045s; 1023s; 949m; 858m; 784m; 698s. ¹H-NMR (300 MHz, CDCl₃):7.19 (d, J=2.1, 1 H, H_(arom, Cat.)); 7.40-7.42 (m, 6 H,H_(arom, Ketal)); 7.58-7.62 (m, 5 H, H_(arom, Cat.), H_(arom, Ketal)).¹³C-NMR (75 MHz, CDCl₃): 112.7; 112.8; 116.4; 119.5; 125.4; 126.3;128.4; 129.5; 138.9; 148.3; 149.3; 167.9. HR-MS (MALDI): calcd. forC₂₀H₁₄BrO₄ ([M+H]⁺): 397.0075, found 397.0078. Anal. calcd. forC₂₀H₁₃BrO₄; C 60.47, H 3.30. found C 60.40; H 3.35.

c) 6-Bromo-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (200 mg, 0.503mmol, 1.4 eq.), EDC.HCl (145 mg, 0.755 mmol, 2.1 eq.),N-hydroxy-succinimide (76 mg, 0.654 mmol, 1.8 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(120 mg, 0.361 mmol, 1 eq.) and Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 166 mg (65%). Colorless foam. Mp.: 116° C. IR (KBr): 3424m; 3170br, w; 2985w; 1636s; 1594s; 1531m; 1495s; 1423w; 1373w; 1236s; 1207s;1156w; 1082s; 1016m; 867w; 778w; 698m. ¹H-NMR (300 MHz, CDCl₃): 1.38 (s,3 H, CH_(3-exo)); 1.62 (s, 3 H, CH_(3-endo)); 4.04 (m, 2 H, H—C(7′),H—C(7″)); 4.69 (m, 1 H, H—C(4′)); 4.95 (dd; J=6.3, 3.6, 1 H, H—C(3′));5.45 (dd, J=6.3, 2.3, 1 H, H—C(2′)); 5.84 (m, 2 H, H—C(5′), H—C(6′));5.96 (bs, 2 H, NH₂); 6.09 (d, J=2.3, 1 H, H—C(1′)); 7.05 (t, J=5.6, 1 H,NHCO); 7.15 (d, J=2.0, 1 H, H_(arom, Cat.)); 7.35-7.40 (m, 6 H,H_(arom, Ketal)); 7.44-7.50 (m, 4 H, H—C(6), H_(arom, Ketal)); 7.72 (d,J=2.0, 1 H, H_(arom, Cat.)); 7.87 (s, 1 H, H—C(8)); 8.20 (s, 1 H,H—C(2)). ¹³C-NMR (75 MHz, CDCl₃): 25.5; 27.3; 40.9; 84.1; 84.5; 87.1;90.3; 114.0; 114.7; 115.2; 116.3; 119.5; 120.1; 125.0; 126.3; 128.4;129.8; 130.5; 138.3; 140.1; 144.1; 148.1; 149.2; 151.7; 154.7; 162.0.HR-MS (MALDI): calcd. for C₃₅H₃₂BrN₆O₆ ([M+H]⁺): 711.1567, found711.1553. Anal. calcd. for C₃₅H₃₁BrN₆O₆: C 59.08, H 4.39, N 11.81. foundC 59.06, H 4.54, N 11.62.

d)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-bromo-2,3-dihydroxy-benzamide

The protected precusor (50 mg, 0.07 mmol) was deprotected according toGP8.

Yield: 18 mg (52%). Colorless solid. t_(R, analyt.): 13.4 min. Mp.: 123°C. (dec.). IR (KBr): 3396 br, m; 1699s; 1637m; 1467w; 1426w; 1325w;1203s; 1135m; 1050w. ¹H-NMR (500 MHz, CD₃OD): 4.03 (m, 2 H, H—C(7′),H—C(7″)); 4.23 (t, J=5.0, 1 H, H—C(4′)); 4.52 (m; 1 H, H—C(3′)); 4.72(t, J=4.8, 1 H, H—C(2′)); 5.92-5.94 (m, 2 H, H—C(5′); H—C(6′)); 6.06 (d,J=4.8, H—C(1′)); 7.05 (d, J=2.3, 1 H, H_(arom, Cat.)); 7.43 (d, J=2.3, 1H, H—C_(arom, Cat.)); 8.27 (s, 1 H, H—C(8)); 8.39 (s, 1 H, H—C(2)).¹³C-NMR (125 MHz, CD₃OD): 41.6; 75.2; 75.6; 86.1; 90.6; 111.2; 118.2;120.7; 121.3; 122.3; 130.3; 130.9; 143.4; 147.8; 148.8; 149.6; 150.2;153.5; 169.9. HR-MS (MALDI): calcd. for C₁₉H₂₀BrN₆O₆ ([M+H]⁺): 507.0628,found 507.0627.

EXAMPLE 3 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-cyano-2,3-dihydroxy-benzamidea) Methyl 6-cyano-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

To a solution of methyl6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (800 mg, 1.95 mmol,1 eq.) in a mixture of 15 mL benzene and 5 mL DMF, Pd(PPh₃)₄ (225 mg,0.195 mmol, 0.1 eq.), KCN (127 mg, 1.95 mmol, 1 eq.) and 18-crown-6 (415mg, 1.56 mmol, 0.8 eq.) was added and the reaction mixture was stirredat 100° C. overnight. Then the reaction mixture was poured into aseparatory funnel containing EtOAc and H₂O and the aqueous phase wasextracted with EtOAc (2×20 mL). The combined organic phases were washedwith H₂O, then saturated aqueous NaCl solution, dried over MgSO₄, andevaporated under reduced pressure. Flash chromatography on silica gel(hexane/EtOAc=20:1→9:1) afforded the desired compound as a colorlesssolid.

Yield: 530 mg (76%). Mp.: 141° C. IR (KBr): 3051w; 2951w; 2228m (CN);1713s (CO); 1470s; 1375m; 1264s; 1225s; 1045s; 917m; 786s. ¹H-NMR (300MHz, CDCl₃): 3.97 (s, 3 H, CH₃); 7.20 (d, J=1.9, 1 H, H_(arom, Cat.));7.39-7.43 (m, 6 H, H_(arom, Ketal)); 7.55-7.58 (m, 4 H,H_(arom, Ketal)); 7.82 (d, J=1.9, 1 H, H_(arom, Cat.)). ¹³C-NMR (75 MHz,CDCl₃): 52.67; 104.8; 113.4; 113.9; 118.0; 120.4; 126.2; 128.4; 129.2;129.7; 138.4; 148.9; 151.5; 163.1. HR-MS (MALDI): calcd. for C₂₂H₁₆NO₄([M+H]⁺): 358.1079, found 358.1071.

b) 6-Cyano-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

To a solution of methyl6-cyano-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (60 mg, 0.168 mmol,1 eq.) in a mixture of 3 mL MeOH and 0.5 mL CH₂Cl₂, a solution ofLiOH.H₂O (21 mg, 0.5 mmol, 3 eq.) in 3 mL H₂O was added. The reactionmixture was vigorously stirred 16 h at r.t., then acidified with 10%AcOH in H₂O and extracted with EtOAc (3×20 mL). The combined organicphases were washed with saturated aqueous NaCl solution, dried overMgSO₄, and the solvents evaporated under reduced pressure to yield thedesired compound as a colorless solid.

Yield: 53 mg (92%). Mp.: 221° C. IR (KBr): 2925m; 2229m; 1696s; 1449s;1267s; 1213s; 1048s; 949m; 922m; 756m; 694s; 641m; 617w. ¹H-NMR (300MHz, CDCl₃): 7.25 (d, J=1.7, 1 H, H_(arom, Cat.)); 7.41 (m, 6 H,H_(arom, Ketal)); 7.58 (m, 4 H, H_(arom, Ketal)); 7.87 (d, J=1.7, 1 H,H_(arom, Cat.)). ¹³C-NMR (75MHz, CDCl₃): 105.0; 112.6; 114.4; 117.8;120.7; 126.1; 128.5; 129.6; 129.8; 138.2; 149.0; 152.1; 167.1. HR-MS(MALDI): calcd. for C₂₁H₁₄NO₄ ([M+H]⁺): 344.0923, found 344.0910.

c) 6-Cyano-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

6-Cyano-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (80 mg, 0.23mmol, 1.5 eq.), EDC.HCl (73 mg, 0.38 mmol, 2.5 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-anyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(50 mg, 0.15 mmol, 1 eq.) and Et₃N (0.05 mL, 0.34 mmol) were reactedaccording to GP7.

Yield: 67 mg (68%). Colorless foam. Mp.: 125° C. IR (KBr): 3428s; 3171w;2986w; 2227w; 1635s; 1597m; 1528m; 1466s; 1374m; 1262s; 1209s; 1082m;1017m; 867w; 762w; 699m; 641w. ¹H-NMR (300 MHz, CDCl₃): 1.38 (s, 3 H,CH_(3-exo)); 1.62 (s, 3 H, CH_(3-endo)); 4.05 (m, 2 H, H—C(7′),H—C(7″)); 4.70 (m, 1 H, H—C(4′)); 4.96 (dd; J=6.3, 3.9, 1 H, H—C(3′));5.46 (dd, J=6.3, 2.0, 1 H, H—C(2′)); 5.79 (bs, 2 H, NH₂); 5.83 (m, 2 H,H—C(5′), H—C(6′)); 6.08 (d, J=2.0, 1 H, H—C(1′)); 7.00 (t, J=5.7, 1 H,NHCO); 7.22 (d, J=1.7, 1 H, H_(arom, Cat.)); 7.38-7.49 (m, 10 H,H_(arom, Ketal)); 7.86 (s, 1 H, H—C(8)); 7.99 (d, J=1.7,H_(arom, Cat.)); 8.19 (s, 1 H, H—C(2)). ¹³C-NMR (75 MHz, CDCl₃): 25.5;27.3; 41.0; 84.1; 84.5; 87.2; 90.3; 105.9; 113.7; 114.7; 116.1; 118.0;120.2; 120.7; 126.3; 128.6; 128.8; 129.1; 130.1; 130.2; 137.6; 140.0;147.8; 148.0; 149.2; 152.3; 155.0; 161.2. HR-MS (MALDI): calcd. forC₃₆H₃₂N₇O₆ ([M+H]⁺): 658.2414, found 658.2403.

d)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-cyano-2,3-dihydroxy-benzamide

The protected precusor (70 mg, 0.11 mmol) was deprotected according toGP8.

Yield: 20 mg (42%). t_(R, analyt.): 9.0 min. IR (KBr): 3396 br, s;2233w; 1703s; 1639s; 1477w; 1441w; 1303m; 1195s; 1137m; 1050w. ¹H-NMR(500 MHz, CD₃OD): 4.06 (d, J=3.7, 2 H, H—C(7′), H—C(7″)); 4.24 (t,J=4.9, 1 H, H—C(4′)); 4.51 (t, J=4.9, 1 H, H—C(3′)); 4.73 (t, J=4.6, 1H, H—C(2′)); 5.94 (m, 2 H, H—C(5′), H—C(6′)); 6.04 (d, J=4.6, 1 H,H—C(1′)); 7.17 (d, J=1.8, 1 H, H_(arom, Cat.)); 7.70 (d, J=1.8, 1 H,H_(arom, Cat.)); 8.23 (s, 1 H, H—C(8)); 8.33 (s, 1 H, H—C(2)). ¹³C-NMR(75 MHz, (CD₃OD+2 drops of DMSO-d₆): 41.7; 75.2; 75.4; 85.9; 90.2;102.6; 117.3; 119.8; 120.5; 121.1; 124.2; 130.5; 130.6; 143.6; 146.3;148.4; 149.9; 154.6; 169.3 (1 peak missing). HR-MS (MALDI): calcd. forC₂₀H₂₀N₇O₆ ([M+H]⁺): 454.1475, found 454.1466.

EXAMPLE 4 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(2,2,2-trifluoro-acetyl)-2,3-dihydroxy-benzamidea) 2,2-Diphenyl-6-(trifluoroacetyl)-1,3-benzodioxole-4-carboxylic acid

6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (200 mg, 0.503mmol, 1 eq.), LiOMe (40 mg, 1 mmol, 2 eq.) and ethyl trifluoroacetate(0.6 mL, 5.03 mmol, 10 eq.) as the electrophile were reacted accordingto GP4, Method A. The crude product was purified using flashchromatography (silica gel, hexane/EtOAc/AcOH 77:20:3) to give the titlecompound as a yellowish solid.

Yield: 79 mg (38%). Mp.: 187° C. IR (KBr): 2925m; 2555m; 1692s; 1635m;1482s; 1254s; 1213s; 1131s; 1048m; 1013m; 987m; 945m; 802m; 760s; 699s.¹H-NMR (300 MHz, CDCl₃); 7.40-7.44 (m, 6 H, H_(arom, Ketal)); 7.59-7.62(m, 4 H, H_(arom, Ketal)); 7.74 (d, J=1.2, 1 H, H_(arom, Cat.)); 8.35(m, 1 H, H_(arom, Cat.)). 13C-NMR (75 MHz, CDCl₃): 111.7; 112.4; 116.5(q, J=289); 121.0; 124.0; 126.2; 128.5; 128.9; 129.8; 138.3; 149.6;154.3; 167.7; 178.1 (q, J=35.2). ¹⁹F-NMR (282 MHz, CDCl₃): −70.72 (s).HR-MS (MALDI): calcd. for C₂₂H₁₄F₃O₅ ([M+H]⁺): 415.0793, found 415.0784.Anal. calcd. for C₂₂H₁₃F₃O₅: C 63.77, H 3.16; found C 63.81, H 3.29.

b)2,2-Diphenyl-6-(2,2,2-trofluoro-acetyl)-benzo[1,3]dioxole-4-carboxylicacid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

GP7, starting from2,2-diphenyl-6-(trifluoroacetyl)-1,3-benzodioxole-4-carboxylic acid (250mg, 0.603 mmol, 1 eq.), EDC.HCl (175 mg, 0.91 mmol, 1.5 eq.),N-hydroxy-succinimide (90 mg, 0.784 mmol, 1.3 eq.) and9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethyl-perhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine (120 mg, 0.361 mmol, 0.6 eq.)provided the title compound as a colorless foam.

Yield: 174 mg (66%). Mp.: 108-110° C. IR (KBr): 3426m; 3199m; 2986w;2227w; 1644s; 1599m; 1534m; 1476m; 1442m; 1378w; 1253s; 1207s; 1151m;1082m; 1017w; 866w; 761w; 699m; 642w. ¹H-NMR (300 MHz, CDCl₃): 1.38 (s,3 H, CH_(3-exo)); 1.62 (s, 3 H, CH_(3-endo)); 4.07 (m, 2 H, H—C(7′),H—C(7″)); 4.68 (m, 1 H, H—C(4′)); 4.97 (dd; J=6.3, 3.6, 1 H, H—C(3′));5.47 (dd, J=6.3, 2.1, 1 H, H—C(2′)); 5.85 (m, 4 H, H—C(5′), H—C(6′),NH₂); 6.08 (d, J=2.1, 1 H, H—C(1′)); 7.03 (t, J=5.7, 1 H, NHCO);7.38-7.45 (m, 6 H, H_(arom, Ketal)); 7.47-7.52 (m, 4 H,H_(arom, Ketal)); 7.69 (d, J=1.7, 1 H, H_(arom, Cat.)); 7.86 (s, 1 H,H—C(8)); 8.21 (s, 1 H, H—C(2)); 8.43 (d, J=1.7, H_(arom, Cat.)). ¹³C-NMR(75 MHz, CDCl₃): 25.5; 27.3; 41.1; 84.1; 84.5; 87.1; 90.2; 111.5; 114.7;115.5; 116.6 (q, J=281); 120.1; 120.9; 124.8; 126.3; 128.2; 128.6;128.8; 130.2; 137.6; 137.7; 139.9; 148.4; 149.2; 150.2; 152.3; 155.0;161.6; 178.5 (q, J=35.5). ¹⁹F-NMR (282 MHz, CDCl₃): −71.24 (s). HR-MS(MALDI): calcd. for C₃₇H₃₂F₃N₆O₇ ([M+H]⁺): 729.2285, found 729.2291.

c)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-(2,2,2-trifluoro-acetyl)-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (100 mg, 0.137 mmol) gave thedesired product as a colorless solid.

Yield: 40 mg (56%). t_(R, analyt.): 11.1 min. IR (KBr): 3370 br, s;1699s; 1640s; 1545w; 1439w; 1326m; 1283m; 1202s; 1142s; 1052w; 724w.¹H-NMR (500 MHz, CD₃OD): 4.05 (d, J=2.2, 2 H, H—C(7′), H—C(7″)); 4.23(t, J=5.0, 1 H, H—C(4′)); 4.52 (m, 1 H, H—C(3′)); 4.72 (t, J=4.9, 1 H,H—C(2′)); 5.94 (m, 2 H, H—C(5′), H—C(6′)); 6.05 (d, J=4.9, 1 H,H—C(1′)); 7.18 (s, 1 H, H—C(8)); 7.57 (m, 1 H, H_(arom, Cat.)); 8.26 (d,J=4.2, 1 H, H_(arom, Cat.)); 8.38 (s, 1 H, H—C(2)). ¹³C-NMR (125 MHz,(CD₃OD): 41.6; 75.2; 75.6; 86.1; 90.5; 116.4; 119.2; 119.3; 120.7; 124.4(q, J=286); 126.4; 130.2; 131.1; 143.1; 147.2; 148.6; 150.3; 151.0;154.0; 170.9 (1 peak missing). HR-MS (MALDI): calcd. for C₂₁H₂₀F₃N₆O₇([M+H]⁺): 525.1346, found 525.1345.

EXAMPLE 5 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(pyridine-4-carbonyl)-2,3-dihydroxy-benzamidea)6-(Hydroxy-pyridin-4-yl-methyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylicacid

6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (1 g, 2.52 mmol,1 eq.), LiOMe (192 mg, 5.04 mmol, 2 eq.) and pyridine-4-carbaldehyde(0.48 mL, 5.03 mmol, 2 eq.) as the electrophile were reacted accordingto GP4, Method A. The crude product was purified using flashchromatography (silica gel, CH₂Cl₂/MeOH 92:8→80:20) to give the titlecompound as a yellow solid.

Yield 350 mg (33%). Mp.: 213-217° C. (dec.). IR (KBr): 3381 br, s;1565s; 1473m; 1410s; 1257s; 1205s; 1047s; 1026m; 948w; 806w; 777m; 698m;642m. ¹H-NMR (300 MHz, (CD₃)₂SO): 5.63 (s, 1 H, H_(benz.)); 6.11 (bs, 1H, OH); 7.04 (s, 1 H, H_(arom, Cat.)); 7.36 (d, J=5.7, 2 H,H_(arom, Pyr.)); 7.40-7.42 (m, 7 H, H_(arom, Cat), H_(arom, Ketal));7.50-7.54 (m, 4 H, H_(arom, Ketal)); 8.46 (d, J=5.7, 1 H,H_(arom, Pry.)). ¹³C-NMR (75 MHz, (CD₃)₂SO): 62.6; 108.2; 116.1; 120.9;121.4; 125.7; 128.2; 129.1; 137.3; 139.5; 139.6; 145.3; 147.0; 149.2;153.6; 189.8. HR-MS (MALDI): calcd. for C₂₆H₂₀NO₅ ([M+H]⁺): 426.1341,found 426.1332.

b) 2,2-Diphenyl-6-(pyridine-4-carbonyl)-1,3-benzodioxole-4-carboxylicacid

To a solution of6-(hydroxy-pyridin-4-yl-methyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylicacid (128 mg, 0.324 mmol, 1 eq.) in a mixture of 10 mL acetone and 3 mLDMSO, IBX (273 mg, 0.973 mmol, 3 eq.) was added and the reaction mixturewas stirred 3 h at 50° C. The mixture was partitioned between H₂O andEtOAc, and the organic layer was washed with saturated NaCl solutionbefore being dried over MgSO₄ and evaporated under reduced pressure toyield the title compound as a yellowish solid.

Yield: 130 mg (95%). Mp.: 256-257° C. IR (KBr): 3447 br, w; 3062w;2426w; 1709m; 1669m; 1624m; 1475m; 1440s; 1408w; 1323w; 1270s; 1211s;1048s; 1017m; 910w; 801w; 759m; 698m; 642m. ¹H-NMR (300 MHz, (CD₃)₂SO):7.45-7.48 (m, 7 H, H_(arom, Cat.), H_(arom, Ketal)); 7.54-7.58 (m, 6 H,H_(arom, Ketal), H_(arom, Pyr).); 7.73 (s, 1 H, H_(arom, Cat.)); 8.77(d, J=4.5, 2 H, H_(arom, Pyr.)). ¹³C-NMR (75 MHz, (CD₃)₂SO): 111.8;112.9; 118.9; 122.4; 125.8; 127.9; 128.6; 129.5; 129.8; 138.2; 144.2;148.4; 149.8; 151.1; 163.9; 192.1. HR-MS (MALDI): calcd. for C₂₆H₁₉NO₅([M+2H]⁺): 425.1263, found 425.1254.

c) 2,2-Diphenyl-6-(pyridine-4-carbonyl)-benzo[1,3]dioxole-4-carboxylicacid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-Diphenyl-6-(pyridine-4-carbonyl)-1,3-benzodioxole-4-carboxylic acid(100 mg, 0.236 mmol, 1 eq.), EDC.HCl (68 mg, 0.354 mmol, 1.5 eq.),N-hydroxy-succinimid (36 mg, 0.307 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(72 mg, 0.215 mmol 0.9 eq.) and Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 98 mg (62%). Colorless foam. Mp.: 122-126° C. IR (KBr): 3427m;1661s; 1596m; 1528m; 1472m; 1435m; 1374w; 1266s; 1208s; 1019w; 867w;780w; 759w; 700w; 647w. ¹H-NMR (300 MHz, CDCl₃): 1.38 (s, 3 H,CH_(3-exo)); 1.62 (s, 3 H, CH_(3-endo)); 4.07 (m, 2 H, H—C(7′),H—C(7″)); 4.72 (m, 1 H, H—C(4′)); 4.93 (dd; J=6.3, 3.6, 1 H, H—C(3′));5.40 (dd, J=6.3, 2.0, 1 H, H—C(2′)); 5.83 (m, 2 H, H—C(5′), H—C(6′));6.10 (d, J=2.0, 1 H, H—C(1′)); 6.55 (bs, 2 H, NH₂); 7.10 (t, J=5.4, 1 H,NHCO); 7.39-7.45 (m, 6 H, H_(arom, Ketal)); 7.51-7.55 (m, 6 H,H—C_(arom, Ketal), H_(arom, pyridyl)); 7.65 (d, J=1.8, 1 H,H_(arom, Cat.)); 7.92 (s, 1 H, H—C(8)); 8.03 (d, J=1.8, H_(arom, Cat.));8.29 (s, 1 H, H—C(2)); 8.79 (dd, J=4.5, 1.8, 2 H, H_(arom, pyridyl)).¹³C-NMR (75 MHz, CDCl₃): 25.5; 27.2; 41.0; 84.2; 84.4; 87.2; 90.4;111.8; 114.6; 114.7; 120.0; 120.4; 122.6; 126.3; 128.0; 128.6; 130.1;130.3; 130.8; 137.9; 138.0; 140.2; 144.3; 148.4; 148.9; 149.1; 150.3;151.0; 154.4; 162.1; 193.0. HR-MS (MALDI): calcd. for C₄₁H₃₆N₇O₇([M+H]⁺): 738.2676, found 738.2677.

d)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(pyridine-4-carbonyl)-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (50 mg, 0.068 mmol) affordedthe desired product as a yellowish solid.

Yield: 18 mg (50%). t_(R, analyt.): 10.9 min. IR (KBr): 3385 br, s;1678s; 1637s; 1432w; 1307m; 1201s; 1132m; 1051w; 835w; 723w. ¹H-NMR (500MHz, CD₃OD): 3.94 (d, J=3.7, 2 H, H—C(7′), H—C(7″)); 4.13 (t, J=5.3, 1H, H—C(4′)); 4.39 (t, J=5.3, 1 H, H—C(3′)); 4.64 (t, J=4.8, 1 H,H—C(2′)); 5.82 (m, 2 H, H—C(5′), H—C(6′)); 5.93 (d, J=4.8, 1 H,H—C(1′)); 7.37 (d, J=2.1, 1 H, H_(arom, Cat.)); 7.57 (dd, J=4.6, 1.6, 2H, H_(arom, Pyr.)); 7.71 (d, J=2.1, 1 H, H_(arom, Cat.)); 8.12 (s, 1 H,H—C(8)); 8.22 (s, 1 H, H—C(2)); 8.65 (dd, J=4.6, 1.6, 2 H,H_(arom, Pyr.)). ¹³C-NMR (125 MHz, CD₃OD): 41.7; 75.1; 75.6; 85.9; 90.5;116.7; 119.6; 120.7; 123.5; 124.5; 127.9; 130.5; 130.7; 142.5; 147.7;148.1; 150.3; 150.4; 150.5; 155.1; 155.7; 170.2; 194.7. HR-MS (MALDI):calcd. for C₂₅H₂₄N₇O₇ ([M+H]⁺): 534.1737, found 534.1729.

EXAMPLE 6 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-cyclohexanecarbonyl-2,3-dihydroxy-benzamidea) 6-Cyclohexanecarbonyl-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (1.26 g, 3.16mmol, 1 eq.), LiOMe (240 mg, 6.32 mmol, 2 eq.) and cyclohexanecarboxylicacid methoxy-methyl-amide (650 mg, 3.8 mmol, 1.2 eq.) as theelectrophile were reacted according to GP4, Method A. The crude productwas purified using flash chromatography (silica gel, hexane/Et2O/AcOH5:1:0.1) and subsequent recrystallization from CH₂Cl₂/hexane to give thetitle compound as a yellowish solid.

Yield: 338 mg (25%). Mp.: 212-214° C. IR (KBr): 3062w; 2932m; 2854m;1693s; 1628w; 1448s; 1250s; 1205s; 1155m; 1042m; 1020m; 988m; 948m;875w; 752m; 695s. ¹H-NMR (300 MHz, CDCl₃): 1.26-1.52 (m, 6 H,CH_(2,cyclohexl)); 1.72-1.86 (m, 4H, CH_(2,cyclohexyl)); 3.24 (m, 1 H,CHCO); 7.38-7.45 (m, 6 H, H_(arom, Ketal)); 7.59-7.65 (m, 4 H,H_(arom, Ketal)); 7.70 (d, J=1.7, 1 H, H_(arom, Cat.)); 8.16 (d, J=1.7,1 H, H_(arom, Cat.)) ¹³C-NMR (75 MHz, CDCl₃): 25.9; 26.0; 29.7; 45.4;110.9; 112.1; 119.8; 125.4; 126.3; 128.4; 129.6; 130.7; 138.8; 149.3;152.4; 168.8; 201.2. HR-MS (MALDI): calcd. for C₂₇H₂₅O₅ ([M+H]⁺):429.1702, found 429.1693.

b) 6-Cyclohexanecarbonyl-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylicacid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-Diphenyl-6-cyclohexanecarbonyl-1,3-benzodioxole-4-carboxylic acid(197 mg, 0.46 mmol, 1 eq.), EDC.HCl (133 mg, 0.69 mmol, 1.5 eq.),N-hydroxy-succinimide (70 mg, 0.6 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(130 mg, 0.391 mmol, 0.85 eq.) and Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 145 mg (50%). Colorless foam. Mp.: 120-122° C. IR (KBr): 3428 br,m; 2931m; 2853w; 1667s; 1636s; 1596m; 1529m; 1473m; 1433m; 1376w; 1252s;1209s; 1154w; 1082m; 1049m; 1018w; 867w; 777w; 699w. ¹H-NMR (300 MHz,CDCl₃): 1.24-1.52 (m, 9 H, CH_(3-exo), CH_(2,cyclohexyl)); 1.62 (s, 3 H,CH_(3-endo)); 1.70-1.86 (m, 4 H, CH_(2,cyclohexyl)); 3.70 (m, 1 H,CHCO); 4.07 (m, 2 H, H—C(7′), H—C(7″)); 4.70 (m, 1 H, H—C(4′)); 4.96(dd; J=6.5, 3.9, 1 H, H—C(3′)); 5.45 (dd, J=6.5, 2.1, 1 H, H—C(2′));5.86 (m, 2 H, H—C(5′), H—C(6′)); 5.92 (bs, 2 H, NH₂); 6.09 (d, J=2.1, 1H, H—C(1′)); 7.11 (t, J=5.4, 1 H, NHCO); 7.36-7.41 (m, 6 H,H_(arom, Ketal)); 7.48-7.52 (m, 4 H, H—C_(arom, Ketal),); 7.65 (d,J=1.5, 1 H, H—C_(arom, Cat.)); 7.87 (s, 1 H, H—C(8)); 8.22 (s, 1 H,H—C(2)); 8.24 (d, J=1.5, H—C_(arom, Cat.)). ¹³C-NMR (75 MHz, CDCl₃):25.4; 25.8; 26.0; 27.2; 29.6; 40.9; 45.3; 84.1; 84.4; 87.1; 90.2; 110.9;114.4; 114.7; 119.7; 120.1; 124.6; 126.3; 128.4; 129.8; 130.4; 131.5;138.1; 138.2; 139.9; 148.0; 148.1; 149.2; 152.0; 154.8; 162.5; 201.8.HR-MS (MALDI): calcd. for C₄₂H₄₃N₆O₇ ([M+H]⁺): 743.3193, found 743.3195.Anal. calcd. for C₄₂H₄₂N₆O₅: C 67.91, H 5.70, N 11.31. found C 67.77, H5.85, N 11.05.

c)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-cyclohexanecarbonyl-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (60 mg, 0.081 mmol) affordedthe desired product as a colorless solid.

Yield: 25 mg (59%). t_(R, analyt.): 14.5 min (linear gradient of CH₃CNin H₂O with 0.1% TFA 15→55% in 20 min.) IR (KBr): 3388 br, s; 2933m;1700s; 1638s; 1543w; 1430w; 1326m; 1295m; 1202s; 1130m; 1048w; 837w;801w; 724w. ¹H-NMR (500 MHz, CD₃OD): 1.23-1.29 (m, 1 H, 3.94CH_(2,cyclohexyl)); 1.38-1.50 (m, 4 H, CH_(2,cyclohexyl)); 1.72-1.83 (m,5 H, CH_(2,cyclohexyl)); 3.35 (t, J=1.6, 1 H, CHCO); 4.08 (d, J=3.3, 2H, H—C(7′), H—C(7″)); 4.25 (t, J=5.0, 1 H, H—C(4′)); 4.52 (t, J=5.0, 1H, H—C(3′)); 4.74 (t, J=4.7, 1 H, H—C(2′)); 5.96 (m, 2 H, H—C(5′),H—C(6′)); 6.04 (d, J=4.7, 1 H, H—C(1′)); 7.53 (d, J=2.0, 1 H,H—C_(arom, Cat.)); 8.02 (d, J=2.0, 1 H, H_(arom, Cat.)); 8.23 (s, 1 H,H—C(8)); 8.34 (s, 1 H, H—C(2)). ¹³C-NMR (125 MHz, CD₃OD): 26.8; 27.1;30.8; 41.7; 46.0; 75.1; 75.6; 86.0; 90.5; 116.4; 118.5; 120.7; 128.6;130.5; 130.9; 142.8; 147.8; 149.7; 150.3; 154.7; 154.9; 170.7; 204.6.HR-MS (MALDI): calcd. for C₂₆H₃₁N₆O₇ ([M+H]⁺): 539.2254, found 539.2244.

EXAMPLE 7 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-chloro-2,3-dihydroxy-benzamidea) Methyl 5-chloro-2,3-dihydroxy-benzoate

5-Chloro-2,3-dihydroxybenzoic acid (290 mg, 1.54 mmol, 1 eq.) and SOCl₂(550 mg, 4.61 mmol, 3 eq.) were reacted according to GP1.

Yield: 250 mg (80%). Gray powder. IR (KBr): 3453s; 3096m; 2960m; 1700s;1673s; 1471s; 1437s; 1316s; 1233s; 1202s; 1152s; 1013m; 932m; 863m;788m; 723m. ¹H-NMR (300 MHz, CDCl₃): 3.96 (s, 3 H, OCH₃); 5.73 (bs, 1 H,OH); 7.10 (d, J=2.1, 1 H, H_(arom, Cat.)); 7.35 (d, J=2.1, 1 H,H_(arom, Cat)); 10.84 (s, 1 H, OH). ¹³C-NMR (75 MHz, CDCl₃): 52.8;112.7; 119.7; 120.0; 124.1; 145.7; 147.6; 169.7. HR-MS (EI): calcd. forC₈H₇ClO₄ ([M+H]⁺): 202.0033, found 201.9774.

b) Methyl 6-chloro-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

Methyl 5-chloro-2,3-dihydroxy-benzoate (330 mg, 1.63 mmol, 1 eq.) anddichlorodiphenyl-methane (470 mg, 1.96 mmol, 1.2 eq.) were reactedaccording to GP2, Method B.

Yield: 310 mg (52%). Colorless solid. Mp.: 151-152° C. IR (KBr): 3086w;2947w; 1719s (CO); 1595w; 1468s; 1445m; 1360m; 1277m; 1245s; 1202s;1166m; 1042m; 1014m; 905w; 866w; 806m; 781m; 762m; 696m. ¹H-NMR (300MHz, CDCl₃): 3.94 (s, 3 H, CH₃); 7.00 (d, J=2.1, 1 H, H_(arom, Cat.));7.38-7.40 (m, 6 H, H_(arom, Ketal), H_(arom, Cat.)); 7.56-7.59 (m, 4 H,H_(arom, Ketal)). ¹³C-NMR (75 MHz, CDCl₃): 52.6; 111.1; 113.3; 119.4;122.3; 126.3; 126.6; 128.6; 129.7; 139.4; 147.4; 149.3; 164.2. HR-MS(MALDI): calcd. for C₂₁H₁₆ClO₄ ([M+H]⁺): 367.0737, found 367.0731. Anal.calcd. for C₂₁H₁₅ClO₄: C 68.77, H 4.12. found C 68.64, H 4.29.

c) 6-Chloro-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

Methyl 6-chloro-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (150 mg,0.408 mmol, 1 eq.) and LiOH.H₂O (52 mg, 1.23 mmol, 3 eq.) were reactedaccording to GP3.

Yield: 117 mg (82%). Colorless solid. Mp.: 206-207° C. IR (KBr):. 3071m;2868m; 2616w; 1704s (CO); 1599w; 1469s; 1450m; 1407w; 1350w; 1284m;1267m; 1238s; 1200s; 1044m; 1022m; 949w; 908w; 859w; 799m; 761m; 698m;642w. ¹H-NMR (300 MHz, CDCl₃): 7.05 (d, J=2.1, 1 H, H_(arom, Cat.));7.39-7.42 (m, 6 H, H_(arom, Ketal)); 7.46 (d, J=2.1, 1 H,H_(arom, Cat.)); 7.58-7.61 (m, 4 H, H_(arom, Ketal)). ¹³C-NMR (75 MHz,CDCl₃): 112.3; 114.1; 119.9; 122.6; 126.5; 126.6; 128.7; 129.8; 139.2;148.1; 149.5; 168.5. HR-MS (MALDI): calcd. for C₂₀H₁₄ClO₄ ([M+H]⁺):353.0581, found 353.0576.

d) 6-Chloro-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

6-Cloro-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (90 mg, 0.255mmol, 1 eq.), EDC.HCl (75 mg, 0.383 mmol, 1.5 eq.),N-hydroxy-succinimide (40 mg, 0.332 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(85 mg, 0.255 mmol, 1 eq.) and Et₃N (0.68 mmol) were reacted accordingto GP7.

Yield: 123 mg (73%). Colorless foam. Mp.: 111-113° C. IR (KBr):. 3424m;3176m; 2986m; 1638s; 1595s; 1530m; 1462s; 1374m; 1329m; 1240s; 1208s;1156w; 1083m; 1047m; 1017m; 971w; 867w; 778w; 698m. ¹H-NMR (300 MHz,CDCl₃): 1.37 (s, 3 H, CH_(3-exo)); 1.61 (s, 3 H, CH_(3-endo)); 4.04 (m,2 H, H—C(7′), H—C(7″)); 4.69 (m, 1 H, H—C(4′)); 4.94 (dd; J=6.3, 3.6, 1H, H—C(3′)); 5.44 (dd, J=6.3, 2.1, 1 H, H—C(2′)); 5.83 (m, 2 H, H—C(5′),H—C(6′)); 6.06 (bs, 2 H, NH₂); 6.08 (d, J=2.1, 1 H, H—C(1′)); 7.00 (d,J=2.1, 1 H, H_(arom, Cat.)); 7.06 (t, J=5.7, 1 H, NHCO); 7.35-7.40 (m, 6H, H_(arom, Ketal)); 7.44-7.50 (m, 4 H, H—C(6), H_(arom, Ketal)); 7.56(d, J=2.1, 1 H, H_(arom, Cat.)); 7.87 (s, 1 H, H—C(8)); 8.19 (s, 1 H,H—C(2)). ¹³C-NMR (75 MHz, CDCl₃): 25.6; 27.4; 41.0; 84.4; 84.7; 87.4;90.5; 112.8; 115.0; 116.1; 119.8; 120.2; 122.3; 126.6; 127.6; 128.6;128.8; 130.2; 130.8; 138.7; 140.4; 143.9; 148.3; 149.5; 152.2; 155.1;162.5. HR-MS (MALDI): calcd. for C₃₅H₃₂ClN₆O₆ ([M+H]⁺): 667.2072, found667.2065.

e)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-chloro-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (70 mg, 0.105 mmol) affordedthe desired product as a colorless solid.

Yield: 35 mg (73%). t_(R, analyt.): 13.1 min. IR (KBr): 3396 br, s;1700s; 1636m; 1542w; 1469w; 1429w; 1326w; 1203s; 1135m; 1050w; 972w;800w; 725w. ¹H-NMR (500 MHz, (CD₃)₂SO): 3.93 (m, 2 H, H—C(7′), H—C(7″));4.09 (t, J=4.9, 1 H, H—C(4′)); 4.35 (m; 1 H, H—C(3′)); 4.64 (t, J=5.1, 1H, H—C(2′)); 5.78-5.89 (m, 2 H, H—C(5′), H—C(6′)); 5.91 (d, J=5.1,H—C(1′)); 6.92 (d, J=2.5, 1 H, H_(arom, Cat.)); 7.41 (d, J=2.5, 1 H,H_(arom, Cat.)); 8.12 (bs, 1 H, OH); 8.23 (s, 1 H, H—C(8)); 8.46 (s, 1H, H—C(2)); 9.02 (t, J=5.4, 1 H, H—NHCO); 12.62 (bs, 1 H, OH). ¹³C-NMR(125 MHz, CD₃OD): 40.1; 73.0; 73.9; 84.3; 87.8; 115.7; 116.5; 118.3;119.1; 121.7; 129.3; 129.4; 141.1; 147.6; 148.8; 148.9; 149.3; 153.4;168.3. HR-MS (MALDI): calcd. for C₁₉H₂₀ClN₆O₆ ([M+H]⁺): 463.1132, found463.1133.

EXAMPLE 8 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(4-fluoro-phenyl)-2,3-dihydroxy-benzamidea) Methyl6-(4-fluoro-phenyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (100 mg,0.243 mmol, 1 eq.), Pd(PPh₃)₄ (15 mg, 0.012 mmol, 0.05 eq.),4-fluorophenylboronic acid (135 mg, 0.972 mmol, 4 eq.) and K₂CO₃ (202 g,1.46 mmol, 6 eq.) were reacted according to GP5.

Yield: 80 mg (78%). Colorless solid. Mp.: 125-127° C. IR (KBr): 3061m;2950m; 1723s (CO); 1634w; 1603m; 1517m; 1472s; 1364m; 1257s; 1215s;1053s; 947m; 833s; 780m; 698s; 640m. ¹H-NMR (300 MHz, CDCl₃): 3.97 (s, 3H, CH₃); 7.10 (tt, J=8.7, 2.0, 2 H, H_(arom, p-F-phenyl)); 7.20 (d,J=2.0, 1 H, H_(arom, Cat.)); 7.39-7.42 (m, 6 H, H_(arom, Ketal));7.45-7.50 (m, 2 H, H_(arom, p-F-phenyl)); 7.59 (d, J=2.0, 1 H,H_(arom, Cat.)); 7.62-7.65 (m, 4 H, H_(arom, Ketal)). ¹³C-NMR (75 MHz,CDCl₃): 52.2; 111.1; 112.7; 115.6 (d, J=21.2); 118.4; 121.1; 126.3;128.2; 128.3; 129.2; 134.0; 136.0; 139.4; 147.4; 148.8; 162.2 (d,J=244.7); 164.8. ¹⁹F-NMR (282 MHz, CDCl₃): −115.9 (tt, J=9.6, 5.4).HR-MS (MALDI): calcd. for C₂₇H₁₉FO₄ ([M]⁺): 426.1267, found 426.1258.

b) 6-(4-Fluoro-phenyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

Methyl 6-(4-fluoro-phenyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylate(250 mg, 0.586 mmol, 1 eq.) and LiOH.H₂O (74 mg, 1.76 mmol, 3 eq.) werereacted according to GP3.

Yield: 214 mg (89%). Colorless solid. Mp.: 215-217° C. IR (KBr): 3032m;2625w; 1687s (CO); 1635w; 1604m; 1519m; 1473s; 1422m; 1355w; 1281s;1219s; 1179m; 1055s; 1022s; 948m; 918w; 832s; 784m; 756m; 699s; 641m.¹H-NMR (300 MHz, CDCl₃): 7.10 (t, J=8.7, 2 H, H_(arom, p-F-phenyl));7.26 (d, J=1.0, 1 H, H_(arom, Cat.)); 7.39-7.43 (m, 6 H,H_(arom, Ketal)); 7.46-7.51 (m, 2 H, H_(arom, p-F-phenyl)); 7.63-7.66(m, 5 H, H_(arom, Ketal), H_(arom, Cat.)). ¹³C-NMR (75 MHz, CDCl₃):111.7; 112.0; 115.7 (d, J=21.2); 118.9; 121.6; 126.3; 128.3; 128.4;129.4; 134.3; 135.9 (d, J=3.1); 139.3; 148.1; 149.0; 162.3 (d, J=245.3);169.0. ¹⁹F-NMR (282 MHz, CDCl₃): −115.7 (tt, J=8.5, 5.4). HR-MS (MALDI):calcd. for C₂₇H₁₉FO₄Na ([M+Na]⁺): 435.1009, found 435.1000.

c) 6-(4-Fluoro-phenyl)-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

6-(4-Fluoro-phenyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (130mg, 0.315 mmol, 1 eq.), EDC.HCl (91 mg, 0.473 mmol, 1.5 eq.),N-hydroxy-succinimide (48 mg, 0.409 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(90 mg, 0.271 mmol, 0.86 eq.) and Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 130 mg (66%). Colorless foam. Mp.: 123-125° C. IR (KBr): 3425m;3175w; 2987w; 1636s; 1598m; 1517m; 1469s; 1373w; 1274m; 1213s; 1158w;1082m; 1052m; 1016w; 867w; 834w; 777w; 699m. ¹H-NMR (300 MHz, CDCl₃):1.38 (s, 3 H, CH_(3-exo)); 1.62 (s, 3 H, CH_(3-endo)); 4.08 (m, 2 H,H—C(7′), H—C(7″)); 4.71 (m, 1 H, H—C(4′)); 4.95 (dd; J=6.6, 3.6, 1 H,H—C(3′)); 5.44 (dd, J=6.6, 2.3, 1 H, H—C(2′)); 5.87 (m, 2 H, H—C(5′),H—C(6′)); 5.93 (bs, 2 H, NH₂); 6.09 (d, J=2.3, 1 H, H—C(1′)); 7.10 (tt,J=8.7, 2.1, 2 H, H_(arom, p-F-phenyl)); 7.12 (t, J=5.6, 1 H, NHCO); 7.22(d, J=1.8, 1 H, H—C_(arom, Cat.)); 7.37-7.41 (m, 6 H, H_(arom, Ketal));7.47-7.56 (m, 6 H, H_(arom, Ketal), H_(arom, p-F-phenyl)); 7.77 (d,J=1.8, H_(arom, Cat.)); 7.87 (s, 1 H, H—C(8)); 8.19 (s, 1 H, H—C(2)).¹³C-NMR (75 MHz, CDCl₃): 25.5; 27.3; 40.9; 84.1; 84.5; 87.1; 90.3;110.6; 114.7; 115.3; 115.6 (d, J=21.2); 118.8; 120.1; 121.0; 126.4;128.2; 128.4; 128.5; 129.7; 130.7; 135.0; 136.1; 138.7; 139.9; 144.1;147.8; 149.2; 152.0; 154.8; 162.3 (d, J=244.7); 163.1. ¹⁹F-NMR (282 MHz,CDCl₃): −115.9 (tt, J=8.5, 5.4). HR-MS (MALDI): calcd. for C₄₁H₃₅FN₆O₆Na([M+Na]⁺): 749.2500, found 749.2501.

d)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(4-fluoro-phenyl)-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (70 mg, 0.096 mmol) affordedthe desired product as a colorless solid.

Yield: 28 mg (56%). t_(R, analyt.): 17.8 min. IR (KBr): 3407 br, s;1700s; 1641m; 1542w; 1479w; 1314w; 1204s; 1137m; 1050w; 835w; 801w;725w. ¹H-NMR (500 MHz, CD₃OD): 4.07 (m, 2 H, H—C(7′), H—C(7″)); 4.24 (t,J=5.3, 1 H, H—C(4′)); 4.52 (t, J=5.3, 1 H, H—C(3′)); 4.73 (t, J=4.8, 1H, H—C(2′)); 5.96 (bd, J=3.3, 2 H, H—C(5′), H—C(6′)); 6.05 (d, J=4.8, 1H, H—C(1′)); 7.13 (t, J=8.8, 2 H, H_(arom, p-F-phenyl)); 7.20 (d, J=2.0,1 H, H—C_(arom, Cat.)); 7.51 (d, J=2.0, 1 H, H_(arom, Cat.)); 7.58 (dd,J=8.8, 5.4, 2 H, H_(arom, p-F-phenyl)); 8.23 (s, 1 H, H—C(8)); 8.37 (s,1 H, H—C(2)). ¹³C-NMR (125 MHz, CD₃OD): 41.7; 75.2; 75.6; 86.1; 90.5;116.4 (d, J=21.3); 117.0; 117.1; 118.2; 129.3; 129.4; 130.3; 131.0;132.3; 138.1; 143.0; 147.8; 149.0; 152.6; 149.8; 163.6 (d, J=242.5);171.2. HR-MS (MALDI): calcd. for C₂₅H₂₄FN₆O₆ ([M+H]⁺): 523.1741, found523.1731.

EXAMPLE 9 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-p-tolyl-2,3-dihydroxy-benzamidea) Methyl 2,2-diphenyl-6-p-tolyl-1,3-benzodioxole-4-carboxylate

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (500 mg,1.215 mmol, 1 eq.) Pd(PPh₃)₄ (70 mg, 0.06 mmol, 0.05 eq.),p-tolylboronic acid (330 mg, 2.43 mmol, 2 eq.) and K₂CO₃ (1 g, 7.29mmol, 6 eq.) were reacted according to GP5.

Yield: 403 mg (79%). Colorless solid. Mp.: 159-160° C. IR (KBr): 3034w;2941w; 1719s; 1470s; 1450s; 1429m; 1363w; 1255s; 1209s; 1161m; 1053s;1028s; 944w; 817m; 775m; 702s; 640m. ¹H-NMR (300 MHz, CDCl₃): 2.38 (s, 3H, CH₃); 3.97 (s, 3 H, OCH₃); 7.22 (d, J=7.8, 2 H, H_(arom, p-tolyl));7.26 (d, J=1.8, 1 H, H_(arom, Cat.)); 7.38-7.44 (m, 8 H,H_(arom, p-tolyl), H_(arom, Ketal)); 7.62-7.66 (m, 5 H, H_(arom, Cat.),H_(arom, Ketal)). ¹³C-NMR (75 MHz, CDCl₃): 21.2; 52.2; 111.1; 112.7;118.2; 121.0; 126.3; 126.6; 128.2; 129.2; 129.4; 135.0; 136.9; 137.0;139.6; 147.3; 148.7; 164.9. HR-MS (MALDI): calcd. for C₂₈H₂₂O₄Na([M+Na]⁺): 445.1416, found 445.1406.

b) 2,2-Diphenyl-6-p-tolyl-1,3-benzodioxole-4-carboxylic acid

Methyl 2,2-diphenyl-6-p-tolyl-1,3-benzodioxole-4-carboxylate (280 mg,0.662 mmol, 1 eq.) and LiOH.H₂O (84 mg, 2 mmol, 3 eq.) were reactedaccording to GP3.

Yield: 251 mg (93%). Colorless solid. Mp.: 223-224° C. IR (KBr): 3030m;2624m; 1684s (CO); 1634m; 1602w; 1473s; 1421m; 1355w; 1282s; 1213s;1055s; 1023s; 947m; 918w; 871w; 814m; 784m; 758m; 699s; 640m. ¹H-NMR(300 MHz, CDC1₃): 2.39 (s, 3 H, CH₃); 7.23 (d, J=7.8, 2 H,H_(arom, p-tolyl)); 7.31 (d, J=1.8, 1 H, H_(arom, Cat.)); 7.39-7.45 (m,8 H, H_(arom, Ketal), H_(arom, p-tolyl)); 7.64-7.67 (m, 4 H,H_(arom, Ketal)); 7.71 (d, J=1.8, 1 H, H_(arom, Cat.)) ¹³C-NMR (75 MHz,CDCl₃): 21.1; 111.8; 112.0; 118.7; 121.5; 126.4; 126.7; 128.4; 129.4;129.5; 135.3; 136.9; 137.2; 139.5; 148.0; 149.0; 169.4. HR-MS (MALDI):calcd. for C₂₇H₂₀O₄Na ([M+Na]⁺): 431.1259, found 431.1259.

c) 2,2-diphenyl-6-p-tolyl-benzo[1,3]dioxole-4-carboxylic acid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-diphenyl-6-p-tolyl-1,3-benzodioxole-4-carboxylic acid (164 mg, 0.4mmol, 1 eq.), EDC.HCl (115 mg, 0.6 mmol, 1.5 eq.), N-hydroxy-succinimide(60 mg, 0.52 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(90 mg, 0.271 mmol, 0.68 eq.) and Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 111 mg (57%). Colorless foam. Mp.: 124-126° C. IR (KBr): 3423m;3176m; 2986w; 1638s; 1597s; 1531m; 1469s; 1434m; 1373w; 1329w; 1276s;1207s; 1156w; 1081m; 1052s; 1016m; 970w; 867m; 818m; 777m; 699m; 641m.¹H-NMR (300 MHz, CDCl₃): 1.38 (s, 3 H, CH_(3-exo)); 1.62 (s, 3 H,CH_(3-endo)); 2.37 (s, 3 H, CH₃); 4.09 (m, 2 H, H—C(7′), H—C(7″)); 4.71(m, 1 H, H—C(4′)); 4.94 (dd; J=6.5, 3.6, 1 H, H—C(3′)); 5.42 (dd, J=6.5,2.6, 1 H, H—C(2′)); 5.86 (m, 2 H, H—C(5′), H—C(6′)); 6.06 (bs, 2 H,NH₂); 6.09 (d, J=2.6, 1 H, H—C(1′)); 7.17 (t, J=5.6, 1 H, NHCO); 7.21(d, J=8.3, 2 H, H_(arom, p-tolyl)); 7.26 (d, J=1.8, 1 H,H_(arom, Cat.)); 7.36-7.42 (m, 6 H, H_(arom, Ketal)); 7.46 (d, J=8.3, 2H, H_(arom, p-tolyl)); 7.51-7.56 (m, 4 H, H_(arom, Ketal)); 7.82 (d,J=1.8, H—C_(arom, Cat.)); 7.88 (s, 1 H, H—C(8)); 8.19 (s, 1 H, H—C(2)).¹³C-NMR (75 MHz, CDCl₃): 25.2; 25.5; 27.2; 40.8; 84.1; 84.4; 87.1; 90.3;110.5; 114.7; 115.2; 118.6; 120.0; 120.8; 126.4; 126.6; 128.0; 128.3;129.4; 129.6; 130.8; 135.9; 136.0; 137.0; 138.8; 140.0; 143.8; 147.7;149.1; 151.5; 154.6; 163.2. HR-MS (MALDI): calcd. for C₄₂H₃₈N₆O₆Na([M+Na]⁺): 745.2751, found 745.2750. Anal. calcd. for C₄₂H₃₈N₆O₆: C69.79, H 5.30, N 11.63. found C 69.61, H 5.56, N 11.93.

d)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-p-tolyl-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (70 mg, 0.097 mmol) affordedthe desired product as a colorless solid.

Yield: 28 mg (56%). t_(R, analyt.): 18.3 min. IR (KBr): 3397 br, s;1700s; 1640m; 1541w; 1478w; 1430w; 1319w; 1203s; 1137m; 1050w; 973w;799w; 725w. ¹H-NMR (500 MHz, (CD₃)₂SO): 3.97 (m, 2 H, H—C(7′), H—C(7″));4.10 (t, J=4.9, 1 H, H—C(4′)); 4.37 (t; J=4.9, 1 H, H—C(3′)); 4.64 (t,J=5.1, 1 H, H—C(2′)); 5.83-5.90 (m, 2 H, H—C(5′), H—C(6′)); 5.91 (d,J=5.1, H—C(1′)); 7.20 (d, J=1.9, 1 H, H_(arom, Cat.)); 7.22 (d, J=8.0, 1H, H_(arom p-tolyl)); 7.51 (d, J=8.0, 1 H, H_(arom, p-tolyl)); 7.63 (d,J=1.9, 1 H, H_(arom, Cat.)); 8.12 (bs, 1 H, OH); 8.23 (s, 1 H, H—C(8));8.47 (s, 1 H, H—C(2)); 9.16 (t, J=5.5, 1 H, H—NHCO); 12.79 (bs, 1 H,OH). ¹³C-NMR (125 MHz, (CD₃)₂SO): 20.6; 40.1; 73.0; 73.9; 84.2; 87.7;114.8; 114.9; 116.8; 119.0; 125.9; 129.3; 129.5; 130.1; 136.0; 136.7;141.0; 146.5; 148.9; 149.2; 149.4; 153.5; 169.6. HR-MS (MALDI): calcd.for C₂₆H₂₆N₆O₆Na ([M+Na]⁺): 541.1812, found 541.1810.

EXAMPLE 10 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-thiazol-2-yl-2,3-dihydroxy-benzamidea) Methyl 2,2-diphenyl-6-thiazol-2-yl-1,3-benzodioxole-4-carboxylate

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (250 mg,0.608 mmol, 1 eq.) Pd(PPh₃)₄ (70 mg, 0.06 mmol, 0.1 eq.),bis(pinacolato)diboron (200 mg, 0.79 mmol, 1.3 eq.) and KOAc (90 mg,0.912 mmol, 1.5 eq.), then Pd(PPh₃)₄ (70 mg, 0.06 mmol, 0.1 eq.),2-bromo-thiazole (110 mg, 0.67 mmol, 1.1 eq.) and K₂CO₃ (420 mg, 3.04mmol, 5 eq.) were used according to GP6 to yield the title product as acolorless solid.

Yield: 166 mg (66%). Mp.: 154-155° C. IR (KBr): 3054w; 2947w; 1712s(CO); 1627w; 1497w; 1468s; 1447s; 1359m; 1321w; 1286m; 1254s; 1212s;1047s; 1017s; 944w; 929w; 883w; 801m; 781m; 760m; 699s; 641m. ¹H-NMR(300 MHz, CDCl₃): 3.97 (s, 3 H, OCH₃); 7.28 (d, J=3.2H.H_(arom, thiazolyl)); 7.37-7.42 (m, 6 H, H_(arom, Ketal)); 7.60-7.63 (m,4 H, H_(arom, Ketal)); 7.71 (d, J=2.3, 1 H, H_(arom, Cat.)); 7.81 (d,J=3.2, 2 H, H_(arom, thiazolyl)); 8.01 (d, J=2.3, 1 H, H_(arom, Cat.)).¹³C-NMR (75 MHz, CDCl₃): 52.5; 110.4; 113.1; 118.9; 119.4; 122.2; 126.6;127.8; 128.6; 129.7; 139.5; 143.5; 149.4; 149.9; 164.6; 167.4. HR-MS(MALDI): calcd. for C₂₄H₁₈NO₄S ([M+H]⁺): 416.0957, found 416.0947.

b) 2,2-diphenyl-6-thiazol-2-yl-1,3-benzodioxole-4-carboxylic acid

Methyl 2,2-diphenyl-6-thiazol-2-yl-1,3-benzodioxole-4-carboxylate (300mg, 0.722 mmol, 1 eq.) and LiOH.H₂O (91 mg, 2.17 mmol, 3 eq.) werereacted according to GP3.

Yield: 280 mg (96%). Colorless solid. Mp.: 226-227° C. IR (KBr): 3122w;2924w; 1702m (CO); 1629w; 1477s; 1446s; 1319w; 1266s; 1235m; 1213s;1133s; 1048m; 1018m; 948w; 909w; 851w; 792m; 762w; 720w; 699m; 641w.¹H-NMR (300 MHz, (CD₃)₂SO): 7.46-7.50 (m, 6 H, H_(arom, Ketal));7.34-7.57 (m, 4 H, H_(arom, Ketal)); 7.76 (d, J=3.0, 2 H,H_(arom, thiazolyl)); 7.78 (d, J=1.8 1 H, H_(arom, Cat.)); 7.89 (d,J=3.0, 2 H, H_(arom, thiazolyl)); 7.92 (d, J=1.8, 1 H, H_(arom, Cat.)).¹³C-NMR (75 MHz, CDCl₃): 109.7; 113.8; 118.3; 120.4; 121.3; 125.9;127.3; 128.7; 129.7; 138.7; 143.7; 148.4; 148.5; 164.4; 165.7. HR-MS(MALDI): calcd. for C₂₃H₁₆NO₄S ([M+H]⁺): 402.0800, found 402.0794.

c) 2,2-diphenyl-6-thiazol-2-yl-benzo[1,3]dioxole-4-carboxylic acid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-diphenyl-6-thiazol-2-yl-1,3-benzodioxole-4-carboxylic acid (160 mg,0.4 mmol, 1 eq.), EDC.HCl (115 mg, 0.6 mmol, 1.5 eq.),N-hydroxy-succinimide (60 mg, 0.52 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(100 mg, 0.3 mmol, 0.75 eq.) and Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 158 mg (74%). Colorless foam. Mp.: 132° C. IR (KBr): 3424m;3199w; 2987w; 1639s; 1598m; 1532m; 1471m; 1440m; 1374w; 1329w; 1263m;1212s; 1156w; 1081m; 1050m; 1015m; 867w; 779w; 700m; 643w. ¹H-NMR (300MHz, CDCl₃): 1.39 (s, 3 H, CH_(3-exo)); 1.62 (s, 3 H, CH_(3-endo)); 4.08(m, 2 H, H—C(7′), H—C(7″)); 4.76 (m, 1 H, H—C(4′)); 4.93 (dd; J=6.2,3.0, 1 H, H—C(3′)); 5.42 (dd, J=6.2, 2.0, 1 H, H—C(2′)); 5.82 (m, 2 H,H—C(5′), H—C(6′)); 6.10 (d, J=2.0, 1 H, H—C(1′)); 6.63 (bs, 2 H, NH₂);7.12 (t, J=5.7, 1 H, NHCO); 7.30 (d, J=3.5, 2 H, H_(arom, thiazolyl));7.37-7.43 (m, 6 H, H—C_(arom, Ketal)); 7.50-7.54 (m, 4 H,H_(arom, Ketal)); 7.73 (d, J=1.7, 1 H, H—C_(arom, Cat.)); 7.81 (d,J=3.5, 2 H, H_(arom, thiazolyl)); 7.92 (s, 1 H, H—C(8)); 8.14 (d, J=1.7,H—C_(arom, Cat.)); 8.20 (s, 1 H, H—C(2)). ¹³C-NMR (75 MHz, CDCl₃): 25.4;27.1; 40.9; 84.3; 84.4; 87.3; 90.7; 109.7; 114.6; 115.4; 119.0; 119.3;119.9; 121.9; 126.4; 127.9; 128.4; 128.6; 129.8; 130.8; 138.4; 140.5;143.3; 145.9; 148.0; 148.9; 149.5; 153.8; 162.6; 167.2. HR-MS (MALDI):calcd. for C₃₈H₃₃N₇O₆SNa ([M+Na]⁺): 738.2111, found 738.2095. Anal.calcd. for C₄₂H₃₈N₆O₆: C 63.76, H 4.65, N 13.70, found C 63.55, H 4.70,N 13.68.

d)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-thiazol-2-yl-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (80 mg, 0.112 mmol) affordedthe desired product as a colorless solid.

Yield: 43 mg (75%). t_(R, analyt.): 13.1 min. IR (KBr): 3402 br, s;1700s; 1642m; 1597m; 1552w; 1428w; 1318w; 1293w; 1200s; 1136m; 1050w;837w; 800w; 723m. ¹H-NMR (500 MHz, (CD₃)₂SO): 3.97 (m, 2 H, H—C(7′),H—C(7″)); 4.10 (t, J=4.9, 1 H, H—C(4′)); 4.37 (dd, J=5.0, 4.9, 1 H,H—C(3′)); 4.63 (t, J=5.0, 1 H, H—C(2′)); 5.82-5.91 (m, 2 H, H—C(5′),H—C(6′)); 5.92 (d, J=5.0, H—C(1′)); 7.53 (d, J=1.7, 1 H,H_(arom, Cat.)); 7.68 (d, J=3.3, 1 H, H_(arom, thiazolyl)); 7.83 (d,J=3.3, 1 H, H_(arom, thiazolyl)); 7.92 (d, J=1.7, 1 H, H_(arom, Cat.));8.52 (s, 1 H, H—C(8)); 8.56 (bs, 1 H, OH); 9.27 (t, J=5.7, 1 H, H—NHCO);9.71 (s, 1 H, H—C(2)); 12.98 (bs, 1 H, OH). ¹³C-NMR (125 MHz, (CD₃)₂SO):40.1; 73.2; 73.9; 84.3; 87.8; 115.5; 115.8; 115.9; 119.0; 119.6; 123.8;129.3; 129.6; 141.4; 143.4; 146.8; 148.4; 148.8; 151.5; 152.7; 167.0;168.9. HR-MS (MALDI): calcd. for C₂₂H₂₁N₇O₆SNa ([M+Na]⁺): 534.1172,found 534.1173.

EXAMPLE 11 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-benzothiazol-2-yl-2,3-dihydroxy-benzamidea) Methyl6-benzothiazol-2-yl-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (600 mg,1.459 mmol, 1 eq.), Pd(PPh₃)₄ (85 mg, 0.073 mmol, 0.05 eq.),bis(pinacolato)diboron (480 mg, 1.9 mmol, 1.3 eq.) and KOAc (216 mg, 2.2mmol, 1.5 eq.), then Pd(PPh₃)₄ (85 mg, 0.073 mmol, 0.05 eq.),2-bromo-1,3-benzothiazole (375 mg, 1.75 mmol, 1.2 eq.) and K₂CO₃ (1 g,7.3 mmol, 5 eq.) were used according to GP6 to yield the title productas a colorless solid.

Yield: 274 mg (41%). Mp.: 184-185° C. IR (KBr): 3055w; 2950w; 1718s;1635w; 1502w; 1446s; 1368m; 1297m; 1239s; 1212s; 1163m; 1047s; 1015s;945m; 921m; 874m; 795m; 776s; 759s; 723w; 701s; 640m. ¹H-NMR (300 MHz,CDCl₃): 4.00 (s, 3 H, OCH₃); 7.38-7.51 (m, 8 H, H_(arom, benzothiazole),H_(arom, Ketal)); 7.62-7.64 (m, 4 H, H_(arom, Ketal)); 7.86 (d, J=1.7, 1H, H_(arom, Cat.)); 7.88 (d, J=9.3, 1 H, H_(arom, benzothiazole)); 8.04(d, J=9.3, 1 H, H_(arom, benzothiazole)); 8.13 (d, J=1.7, 1 H,H_(arom, Cat.)). ¹³C-NMR (75 MHz, CDCl₃): 52.4; 110.6; 112.8; 119.3;121.5; 122.9; 123.2; 125.1; 126.3; 127.5; 128.3; 129.4; 134.8; 139.1;149.1; 150.2; 153.7; 164.1; 166.5. HR-MS (MALDI): calcd. for C₂₈H₂₀NO₄S([M+H]⁺): 466.1113, found 466.1113. Anal. calcd. for C₂₈H₁₉NO₄S: C72.24, H 4.11, N 3.01. found C 72.15, H 4.03, N 3.19.

b) 2,2-diphenyl-6-benzothiazol-2-yl-1,3-benzodioxole-4-carboxylic acid

Methyl 2,2-diphenyl-6-benzothiazol-2-yl-1,3-benzodioxole-4-carboxylate(210 mg, 0.451 mmol, 1 eq.) and LiOH.H₂O (57 mg, 1.35 mmol, 3 eq.) werereacted according to GP3.

Yield: 201 mg (99%). Colorless solid. Mp.: 227° C. IR (KBr): 3437w;2965w; 2610w; 1738m; 1688s; 1634w; 1460s; 1427m; 1360w; 1256s; 1237s;1211s; 1047s; 1048m; 1015m; 999m; 928w; 878w; 788m; 760m; 726w; 699m;641w. ¹H-NMR (300 MHz, CDCl₃): 7.36-7.44 (m, 7 H,H_(arom, benzothiazole), H_(arom, Ketal)); 7.46-7.53 (m, 1 H,H_(arom, benzothiazole)); 7.53-7.67 (m, 4 H, H_(arom, Ketal)); 7.88(d,J=1.8, 1 H, H_(arom, Cat.)); 7.89 (d, J=8.7, 1 H,H_(arom, benzothiazole)); 8.15 (d, J=8.7, 1 H, H_(arom, benzothiazole));8.28 (d, J=1.8, 1 H, H_(arom, Cat.)). ¹³C-NMR (75 MHz, CDCl₃): 111.4;112.2; 119.7; 121.5; 123.1; 123.7; 125.2; 126.3; 126.4; 127.5; 128.3;129.5; 134.6; 138.9; 149.3; 150.9; 153.6; 166.6; 167.8. HR-MS (MALDI):calcd. for C₂₇H₁₈NO₄S ([M+H]⁺): 452.0957, found 452.0955.

c) 6-Benzothiazol-2-yl-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-diphenyl-6-benzothiazol-2-yl-1,3-benzodioxole-4-carboxylic acid (170mg, 0.38 mmol, 1 eq.), EDC.HCl (110 mg, 0.565 mmol, 1.5 eq.),N-hydroxy-succinimide (57 mg, 0.49 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(100 mg, 0.3 mmol, 0.8 eq.) Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 151 mg (66%). Colorless foam. Mp.: 138-140° C. IR (KBr): 3424m;2982w; 1635s; 1596m; 1533m; 1463m; 1436s; 1373w; 1259m; 1208s; 1155w;1081m; 1048m; 1011m; 867w; 759w; 699w; 641w. ¹H-NMR (300 MHz, CDCl₃):1.38 (s, 3 H, CH_(3-exo)); 1.62 (s, 3 H, CH_(3-endo)); 4.07 (m, 2 H,H—C(7′), H—C(7″)); 4.72 (m, 1 H, H—C(4′)); 4.95 (dd; J=6.3, 3.6, 1 H,H—C(3′)); 5.44 (dd, J=6.3, 2.3, 1 H, H—C(2′)); 5.85 (m, 2 H, H—C(5′),H—C(6′)); 6.09 (d, J=2.3, 1 H, H—C(1′)); 6.17 (bs, 2 H, NH₂); 7.13 (t,J=5.7, 1 H, NHCO); 7.34-7.49 (m, 8 H, H_(arom, Ketal),H_(arom, benzoth.)); 7.49-7.55 (m, 4 H, H_(arom, Ketal)); 7.87 (s, 1 H,H—C(8)); 7.88 (d, J=7.8, 2 H, H_(arom, benzoth.)); 7.91 (d, J=1.9, 1 H,H_(arom, Cat.)); 7.81 (d, J=7.8, 2 H, H_(arom, benzoth.)); 8.20 (s, 1 H,H—C(2)); 8.22 (d, J=1.9, H_(arom, Cat.)). ¹³C-NMR (75 MHz, CDCl₃): 25.4;27.2; 40.9; 84.1; 84.4; 87.2; 90.3; 110.1; 114.6; 115.4; 119.5; 120.0;121.5; 122.9; 123.2; 125.1; 126.2; 126.4; 128.3; 128.4; 128.6; 129.8;130.5; 135.0; 138.3; 140.0; 146.7; 148.1; 149.1; 151.5; 153.7; 154.7;162.4; 166.7. HR-MS (MALDI): calcd. for C₄₂H₃₅N₇O₆SNa ([M+Na]⁺):788.2267, found 788.2266.

d)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-benzothiazol-2-yl-2,3-dihydroxybenzamide

GP8, starting from the protected precursor (83 mg, 0.108 mmol) affordedthe desired product as a yellowish solid.

Yield: 38 mg (64%). t_(R, analyt.): 17.7 min. IR (KBr): 3377 br, s;1685s; 1645m; 1544w; 1436m; 1303m; 1202s; 1137m; 834w; 800w; 759w; 724w.¹H-NMR (500 MHz, (CD₃)₂SO): 4.01 (m, 2 H, H—C(7′), H—C(7″)); 4.13 (t,J=4.9, 1 H, H—C(4′)); 4.39 (dd; J=6.7, 4.9, 1 H, H—C(3′)); 4.66 (t,J=5.0, 1 H, H—C(2′)); 5.80-5.96 (m, 2 H, H—C(5′), H—C(6′)); 5.93 (d,J=5.0, H—C(1′)); 7.43 (t, J=8.0, 1 H, H_(arom, benzoth.)); 7.53 (t,J=8.0, 1 H, H_(arom, benzoth.)); 7.68 (d, J=2.0, 1 H, H_(arom, Cat.));8.00 (d, J=8.0, 1 H, H_(arom, benzoth.)); 8.09 (d, J=2.0, 1 H,H_(arom, Cat.);) 8.12 (d, J=8.0, 1 H, H_(arom, benzoth.)); 8.27 (s, 1 H,H—C(8)); 9.37 (t, J=5.3, 1 H, H—NHCO); 9.86 (s, 1 H, H—C(2)); 13.19 (bs,1 H, OH). ¹³C-NMR (125 MHz, (CD₃)₂SO): 40.1; 73.0; 73.9; 84.2; 87.7;115.4; 115.5; 116.4; 119.1; 122.3; 122.4; 123.3; 125.2; 126.6; 129.4;129.5; 134.4; 141.0; 147.0; 149.0; 149.1; 152.6; 153.3; 153.5; 167.0;168.7. HR-MS (MALDI): calcd. for C₂₆H₂₃N₇O₆SNa ([M+Na]⁺): 584.1328,found 584.1330.

EXAMPLE 12 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-pyridin-4-yl-2,3-dihydroxy-benzamidea) Methyl 2,2-diphenyl-6-pyridin-4-yl-1,3-benzodioxole-4-carboxylate

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (400 mg,0.973 mmol, 1 eq.), Pd(PPh₃)₄ (100 mg, 0.087 mmol, 0.09 eq.),bis(pinacolato)diboron (320 mg, 1.26 mmol, 1.3 eq.) and KOAc (150 mg,1.5 mmol, 1.5 eq.), then Pd(PPh₃)₄ (112 mg, 0.097 mmol, 0.1 eq.),2-bromo-pyridine hydrochloride (265 mg, 1.36 mmol, 1.4 eq.) and K₂CO₃(680 mg, 4.9 mmol, 5 eq.) were used according to GP6 to yield the titleproduct as a colorless solid.

Yield: 264 mg (67%). Mp.: 151-152° C. IR (KBr): 3030w; 2954w; 1718s;1635w; 1594m; 1475s; 1439s; 1418m; 1325m; 1291m; 1269s; 1225s; 1180m;1054s; 1038m; 1018m; 947w; 927w; 886w; 815m; 782m; 753w; 703m; 693m;641m. ¹H-NMR (300 MHz, CDCl₃): 3.98 (s, 3 H, OCH₃); 7.31 (d, J=1.8, 1 H,H_(arom, Cat.)); 7.39-7.41 (m, 6 H, H_(arom, Ketal)); 7.48 (dd, J=4.7,1.8, 1 H, H_(arom, pyridyl)); 7.61-7.64 (m, 4 H, H_(arom, Ketal)); 7.75(d, J=1.7, 1 H, H_(arom, Cat.)); 8.63 (dd, J=4.7, 1.8, 1 H,H_(arom pyridyl)). ¹³C-NMR (75 MHz, CDCl₃): 52.6; 110.9; 113.4; 119.4;121.6; 122.3; 126.6; 128.6; 129.8; 131.7; 139.5; 148.0; 149.4; 149.7;149.8 164.9. HR-MS (MALDI): calcd. for C₂₆H₂₀NO₄ ([M+H]⁺): 410.1392,found 410.1383.

b) 2,2-diphenyl-6-pyridin-4-yl-1,3-benzodioxole-4-carboxylic acid

Methyl 2,2-diphenyl-6-pyridin-4-yl-1,3-benzodioxole-4-carboxylate (250mg, 0.61 mmol, 1 eq.) and LiOH.H₂O (80 mg, 1.84 mmol, 3 eq.) werereacted according to GP3.

Yield: 220 mg (92%). Grayish solid. Mp.: 266° C. (dec.). IR (KBr):3446br, w; 3061w; 2447br, w; 1696m; 1632w; 1603m; 1469s; 1440m; 1373w;1326w; 1273s; 1213s; 1182m; 1054s; 1015m; 949w; 92¹w; 906w; 832m; 789w;777w; 765m; 701m; 640w. ¹H-NMR (300 MHz, (CD₃)₂SO): 7.46-7.48 (m, 6 H,H_(arom, Ketal)); 7.52-7.58 (m, 4 H, H_(arom, Ketal)); 7.67 (d, J=4.4, 2H, H_(arom pyridyl)); 7.73 (m, 2 H, H_(arom, Cat.)); 8.59 (d, J=4.4, 2H, H_(arom, pyridyl)). ¹³C-NMR (75 MHz, CDCl₃): 110.7; 113.9; 117.9;120.8; 121.6; 125.8; 128.6; 129.6; 131.1; 138.7; 145.6; 147.8; 148.5;150.0; 164.6. HR-MS (MALDI): calcd. for C₂₅H₁₈NO₄ ([M+H]⁺): 396.1236,found 396.1234.

c) 2,2-Diphenyl-6-pyridin-4-yl-benzo[1,3]dioxole-4-carboxylic acid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

The reaction of2,2-diphenyl-6-pyridin-4-yl-1,3-benzodioxole-4-carboxylic acid (160 mg,0.405 mmol, 1 eq.), EDC.HCl (117 mg, 0.608 mmol, 1.5 eq.),N-hydroxy-succinimide (61 mg, 0.527 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethyl-perhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(100 mg, 0.3 mmol, 0.74 eq.) and Et₃N (0.1 mL, 0.68 mmol) was carriedout in CH₂Cl₂/DMF 1:1 according to GP7.

Yield: 95 mg (45%). Yellowish foam. IR (neat, dropcast from CH₂Cl₂):3321br, w; 2963m; 1696m; 1645m; 1597m; 1530w; 1468s; 1435w; 1374w;1261s; 1213s; 1053s; 867w; 799m; 699m; 642w. ¹H-NMR (300 MHz, CDCl₃):1.37 (s, 3 H, CH_(3-exo)); 1.61 (s, 3 H, CH_(3-endo)); 4.08 (m, 2 H,H—C(7′), H—C(7″)); 4.70 (m, 1 H, H—C(4′)); 4.96 (dd; J=6.3, 3.9, 1 H,H—C(3′)); 5.45 (dd, J=6.3, 2.3, 1 H, H—C(2′)); 5.86 (m, 2 H, H—C(5′),H—C(6′)); 5.98 (bs, 2 H, NH₂); 6.08 (d, J=2.3, 1 H, H—C(1′)); 7.16 (t,J=5.7, 1 H, NHCO); 7.31 (d, J=1.7, 1 H, H_(arom, Cat.)); 7.36-7.42 (m, 6H, H_(arom, Ketal)); 7.47-7.55 (m, 6 H, H_(arom, Ketal),H_(arom, pyridyl)); 7.86 (s, 1 H, H—C(8)); 7.92 (d, J=1.7, 2 H,H_(arom, Cat.)); 8.18 (s, 1 H, H—C(2)); 8.61 (d, J=6.3,H_(arom, pyridyl)). ¹³C-NMR (75 MHz, CDCl₃): 25.6; 27.4; 41.1; 84.3;84.7; 87.4; 90.5; 110.4; 114.9; 116.0; 119.7; 120.4; 121.6; 122.0;126.2; 126.7; 128.8; 130.2; 130.8; 132.8; 138.8; 140.1; 145.9; 147.6;148.6; 149.6; 150.2; 153.0; 155.6; 163.1. HR-MS (MALDI): calcd. forC₄₀H₃₅N₇O₆Na ([M+Na]⁺): 732.2547, found 732.2549.

d)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-pyridin-4-yl-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (35 mg, 0.049 mmol) affordedthe desired product as a yellowish solid.

Yield: 15 mg (63%). Mp.: 133-137° C. (dec.). t_(R, analyt.): 10.6 min.IR (KBr): 3384 br, s; 1684s; 1633m; 1474w; 1431m; 1321m; 1202s; 1134m;832w; 723w. ¹H-NMR (500 MHz, (CD₃)₂SO): 4.02 (m, 2 H, H—C(7′), H—C(7″));4.11 (t, J=4.8, 1 H, H—C(4′)); 4.37 (m; 1 H, H—C(3′)); 4.67 (t, J=5.1, 1H, H—C(2′)); 5.82-5.94 (m, 2 H, H—C(5′), H—C(6′)); 5.91 (d, J=5.1,H—C(1′)); 7.52 (d, J=1.8, 1 H, H_(arom, Cat.)); 7.85 (bs, 1 H, OH); 8.01(d, J=1.8, 1 H, H_(arom, Cat.)); 8.08 (d, J=5.2, 1 H,H_(arom, pyridyl)); 8.17 (s, 1 H, H—C(8)); 8.42 (s, 1 H, H—C(2)); 8.79(d, J=5.2, 1 H, H_(arom, pyridyl)); 9.23 (t, J=5.5, 1 H, H—NHCO); 9.69(bs, 1 H, OH); 13.35 (bs, 1 H, OH). ¹³C-NMR (125 MHz, (CD₃)₂SO): 40.1;72.9; 73.9; 84.1; 87.7; 115.2; 117.0; 117.2; 119.1; 121.8; 124.8; 129.1;129.6; 140.7; 144.9; 147.3; 149.0; 150.3; 152.6; 154.2; 169.2. HR-MS(MALDI): calcd. for C₂₄H₂₃N₇O₆Na ([M+Na]⁺): 528.1608, found 528.1607.

EXAMPLE 13 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(4-methyl-benzyl)-2,3-dihydroxy-benzamidea) Methyl2,2-diphenyl-6-(4-methyl-benzyl)-1,3-benzodioxole-4-carboxylate

Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (200 mg,1.486 mmol, 1 eq.), Pd(PPh₃)₄ (57 mg, 0.049 mmol, 0.1 eq.),bis(pinacolato)diboron (160 mg, 0.632 mmol, 1.3 eq.) and KOAc (72 mg,0.73 mmol, 1.5 eq.), then Pd(PPh₃)₄ (57 mg, 0.049 mmol, 0.1 eq.),1-bromomethyl-4-methyl-benzene (117 mg, 0.63 mmol, 1.3 eq.) and K₂CO₃(336 mg, 2.43 mmol, 5 eq.) were reacted according to GP6 to yield thetitle product as a colorless, very slowly solidifying oil.

Yield: 197 mg (80%). IR (neat): 3030w; 2950w; 1722s; 1636w; 1603w;1477s; 1449s; 1381w; 1251s; 1202s; 1047s; 1019m; 948w; 918w; 829w; 782m;763m; 699m; 642m. ¹H-NMR (300 MHz, CDCl₃): 2.32 (s, 3 H, CH₃); 3.85 (s,2H, CH₂); 3.93 (s, 3H, OCH₃); 6.83 (d, J=1.8, 1 H, H_(arom, Cat.)); 7.06(d, J=8.6, 2 H, H_(arom, p-Tol.)); 7.10 (d, J=8.6, 1 H,H_(arom, p-Tol.)); 7.29 (d, J=1.8, 1 H, H_(arom, Cat.)); 7.35-7.38 (m, 6H, H_(arom, Ketal)); 7.57-7.60 (m, 4 H, H_(arom, Ketal)). ¹³C-NMR (75MHz, CDCl₃): 21.0; 41.1; 52.0; 112.2; 113.1; 117.9; 122.3; 126.3; 128.2;128.7; 129.1; 129.2; 134.9; 135.8; 137.5; 139.8; 146.6; 148.5; 165.2.HR-MS (MALDI): calcd. for C₂₉H₂₄O₄Na ([M+Na]⁺): 459.1572, found459.1573.

b) 2,2-diphenyl-6-(4-methyl-benzyl)-1,3-benzodioxole-4-carboxylic acid

Methyl 2,2-diphenyl-6-(4-methyl-benzyl)-1,3-benzodioxole-4-carboxylate(300 mg, 0.69 mmol, 1 eq.) and LiOH.H₂O (87 mg, 2.06 mmol, 3 eq.) werereacted according to GP3.

Yield: 287 mg (99%). Colorless solid. Mp.: 211-213° C. IR (KBr): 3434br,w; 2904w; 2571w; 1685m; 1638w; 1604w; 1479m; 1464m; 1304m; 1252m; 1209s;1050m; 1027m; 947w; 921w; 828w; 784m; 750w; 797m; 641w. ¹H-NMR (300 MHz,CDCl₃): 2.32 (s, 3 H, CH₃); 3.86 (s, 2H, CH₂); 6.88 (d, J=1.2, 1 H,H_(arom, Cat.)); 7.07 (d, J=8.4, 2 H, H_(arom, p-Tol.)); 7.11 (d, J=8.4,1 H, H_(arom, p-Tol.)); 7.34-7.40 (m, 7 H, H_(arom, Cat.))H_(arom, Ketal)); 7.58-7.62 (m, 4 H, H_(arom, Ketal)). ¹³C-NMR (75 MHz,CDCl₃): 21.0; 41.1; 111.3; 113.9; 118.4; 122.7; 126.4; 128.3; 128.7;129.3; 135.2; 135.9; 137.4; 139.6; 147.3; 148.6; 169.7. HR-MS (MALDI):calcd. for C₂₈H₂₂O₄Na ([M+Na]⁺): 445.1416, found 445.1415.

c) 2,2-Diphenyl-6-(4-methyl-benzyl)-benzo[1,3]dioxole-4-carboxylic acid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-diphenyl-6-(4-methyl-benzyl)-1,3-benzodioxole-4-carboxylic acid (165mg, 0.39 mmol, 1 eq.), EDC.HCl (115 mg, 0.59 mmol, 1.5 eq.),N-hydroxy-succinimide (57 mg, 0.49 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(100 mg, 0.3 mmol, 0.77 eq.) and Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 172 mg (78%). Colorless foam. Mp.: 107-110° C. IR (KBr): 3426m;3176w; 2986w; 1636s; 1597s; 1529m; 1474s; 1440m; 1374w; 1328w; 1254s;1207s; 1156w; 1082m; 1049m; 1020m; 868w; 776w; 699m; 642w. ¹H-NMR (300MHz, CDCl₃): 1.38 (s, 3 H, CH_(3-exo)); 1.62 (s, 3 H, CH_(3-endo)); 2.29(s, 3 H, CH_(3, p-Tol.)); 3.87 (s, 2H, CH_(2, benzyl.)); 4.05 (m, 2 H,H—C(7′), H—C(7″)); 4.71 (m, 1 H, H—C(4′)); 4.91 (dd; J=6.4, 3.6, 1 H,H—C(3′)); 5.38 (dd, J=6.4, 2.4, 1 H, H—C(2′)); 5.83 (m, 2 H, H—C(5′),H—C(6′)); 6.09 (d, J=2.4, 1 H, H—C(1′)); 6.40 (bs, 2 H, NH₂); 6.83 (d,J=1.8, 1 H, H_(arom, Cat.)); 7.07 (s, 4 H, H_(arom, p-tolyl)); 7.14 (t,J=5.7, 1 H, NHCO); 7.33-7.38 (m, 6H, H_(arom, Ketal)); 7.45-7.49 (m, 5H, H_(arom, Ketal), H_(arom, Cat.)); 7.91 (s, 1 H, H—C(8)); 8.16 (s, 1H, H—C(2)). ¹³C-NMR (75 MHz, CDCl₃): 21.1; 25.4; 27.2; 40.7; 41.3; 84.2;84.4; 87.1; 90.4; 112.5; 114.7; 114.8; 118.2; 119.9; 122.1; 126.3;127.7; 128.3; 128.6; 129.1; 129.5; 131.0; 135.7; 136.0; 137.5; 138.9;140.5; 143.0; 147.3; 148.9; 149.8; 153.8; 163.4. HR-MS (MALDI): calcd.for C₄₃H₄₀N₆O₆Na ([M+Na]⁺): 759.2907, found 759.2909. Anal. calcd. forC₄₃H₄₀N₆O₆: C 70.09, H 5.47, N 11.41. found C 69.89, H 5.60, N 11.33.

d)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(4-methyl-benzyl)-2,3-dihydroxybenzamide

GP8, starting from the protected precursor (90 mg, 0.122 mmol) affordedthe desired product as a colorless solid.

Yield: 63 mg (97%). t_(R, analyt.): 15.8 min. IR (KBr): 3384 br, s;1700s; 1640m; 1596m; 1534w; 1513w; 1484w; 1437m; 1324m; 1290w; 1205s;1133m; 1048w; 972w; 836w; 799w. ¹H-NMR (500 MHz, CD₃OD): 2.25 (s, 3 H,ArCH₃); 3.79 (s, 2H, CH_(2, benzyl.)); 4.03 (m, 2 H, H—C(7′), H—C(7″));4.22 (t, J=5.0, 1 H, H—C(4′)); 4.51 (m, 1 H, H—C(3′)); 4.73 (t, J=4.9, 1H, H—C(2′)); 5.93 (m, 2 H, H—C(5′), H—C(6′)); 6.05 (d, J=4.9, H—C(1′));6.76 (d, J=2.1, 1 H, H_(arom, Cat.)); 7.04 (s, 4 H, H_(arom, p-Tol.));7.14 (d, J=2.1, 1 H, H_(arom, Cat.)); 8.17 (s, 1 H, H—C(8)); 8.39 (s, 1H, H—C(2)). ¹³C-NMR (75 MHz, CD₃OD): 21.1; 41.6; 41.9; 75.3; 75.7; 86.2;90.7; 116.5; 118.8; 120.6; 120.8; 129.7; 130.1; 130.2; 131.2; 133.6;136.7; 139.7; 143.5; 147.3; 147.6; 148.5; 150.2; 153.4; 171.3. HR-MS(MALDI): calcd. for C₂₇H₂₈N₆O₆Na ([M+Na]⁺): 555.1968, found 555.1957.

EXAMPLE 14 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-dimethylcarbamoyl-2,3-dihydroxy-benzamidea) 6-Dimethylcarbamoyl-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (200 mg, 0.486mmol), LiH (10 mg, 0.97 mmol, 2 eq.) and dimethylcarbamoylchloride (0.18mL, 1.94 mmol, 4 eq.) as the electrophile were reacted according to GP4,Method B. The crude product was purified using flash chromatography(silica gel, hexane/EtOAc/AcOH 67:30:3) to give the title compound as acolorless solid.

Yield: 40 mg (21%). Mp.: 207-208° C. IR (KBr): 3417w; 2935w; 1718s;1635m; 1607s; 1448s; 1415m; 1247s; 1207s; 1075w; 1041s; 1023s; 949m;881m; 788m; 765m; 701s; 643m. ¹H-NMR (300 MHz, CDCl₃): 3.06 (bs, 6 H,CH₃); 7.20 (d, J=1.5, 1 H, H_(arom, Cat.)); 7.37-7.41 (m, 6 H,H_(arom, Cat.)); 7.56 (d, J=1.5, 1 H, H_(arom, Cat.)); 7.58-7.62 (m, 4H, H_(arom, Ketal)). ¹³C-NMR (75 MHz, CDCl₃): 35.8; 40.0; 111.2; 112.4;119.3; 122.7; 126.4; 128.4; 129.4; 129.5; 139.1; 148.8; 149.8; 168.5;170.1. HR-MS (MALDI): calcd. for C₂₃H₂₀NO₄ ([M+H]⁺): 390.1341, found390.1340.

b) 6-Dimethylcarbamoyl-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

6-Dimethylcarbamol-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (120mg, 0.31 mmol, 1 eq.), EDC.HCl (90 mg, 0.46 mmol, 1.5 eq.),N-hydroxy-succinimide (46 mg, 0.4 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(93 mg, 0.28 mmol, 0.9 eq.) and Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 160 mg (81%). Colorless foam. IR (KBr): 3425m; 3193w; 2932w;1639s; 1528m; 1471m; 1449m; 1396w; 1329w; 1263m; 1208s; 1157w; 1082m;1048m; 1018m; 867w; 781w; 700m; 643w. ¹H-NMR (300 MHz, CDCl₃): 1.38 (s,3 H, CH_(3-exo)); 1.61 (s, 3 H, CH_(3-endo)); 3.02 (bs, 3 H, N(CH₃)₂);3.07 (bs, 3H, N(CH₃)₂); 4.05 (m, 2 H, H—C(7′), H—C(7″)); 4.74 (dd,J=7.2, 3.3, 1 H, H—C(4′)); 4.91 (dd; J=6.5, 3.3, 1 H, H—C(3′)); 5.43(dd, J=6.5, 2.0, 1 H, H—C(2′)); 5.79 (m, 2 H, H—C(5′), H—C(6′)); 6.08(d, J=2.0, 1 H, H—C(1′)); 6.18 (bs, 2 H, NH₂); 7.08 (t, J=5.7, 1 H,NHCO); 7.16 (d, J=1.8, 1 H, H_(arom Cat.)); 7.35-7.42 (m, 6 H,H_(arom, Ketal)); 7.46-7.51 (m, 4 H, H_(arom, Ketal)); 7.69 (d, J=1.8, 1H, H_(arom, Cat.)); 7.82 (s, 1 H, H—C(8)); 8.17 (s, 1 H, H—C(2)).¹³C-NMR (75 MHz, CDCl₃): 25.3; 27.0; 35.5; 39.8; 40.6; 84.4; 84.6; 87.5;90.7; 111.2; 114.5; 114.6; 119.3; 120.1; 122.2; 126.4; 128.0; 128.5;129.8; 130.3; 130.8; 138.5; 139.9; 145.6; 147.5; 149.1; 151.6; 154.8;162.7; 170.3. HR-MS (MALDI): calcd. for C₃₈H₃₈N₇O₇ ([M+H]⁺): 704.2833,found 704.2834.

c)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-dimethylcarbamoyl-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (90 mg, 0.128 mmol) affordedthe desired product as a colorless solid.

Yield: 54 mg (86%). t_(R, analyt.): 7.3 min. IR (KBr): 3385 br, s;1700s; 1605s; 1548w; 1509w; 1478w; 1416w; 1326w; 1296m; 1253w; 1202s;1137m; 1048w; 972w; 838w; 801w; 725w. ¹H-NMR (500 MHz, CD₃OD): 2.96 (bs,6 H, N(CH₃)₂); 3.95 (m, 2 H, H—C(7′), H—C(7″)); 4.14 (t, J=4.9, 1 H,H—C(4′)); 4.42 (t, J=4.9, 1 H, H—C(3′)); 4.66 (t, J=4.8, 1 H, H—C(2′));5.83 (m, 2 H, H—C(5′), H—C(6′)); 5.96 (d, J=4.8, H—C(1′)); 6.92 (d,J=2.0, 1 H, H_(arom, Cat.)); 7.29 (d, J=2.0, 1 H, H_(arom, Cat.)); 8.15(s, 1 H, H—C(8)); 8.31 (s, 1 H, H—C(2)). ¹³C-NMR (125 MHz, CD₃OD): 34.4;38.8; 40.1; 73.7; 74.2; 84.8; 89.3; 115.1; 116.7; 116.8; 119.3; 126.0;128.7; 129.4; 142.4; 145.4; 146.1; 148.6; 150.3; 151.5; 169.0; 171.8.HR-MS (MALDI): calcd. for C₂₂H₂₆N₇O₇ ([M+H]⁺): 500.1894, found 500.1894.

EXAMPLE 15 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-((E)-2-dimethylcarbamoyl-vinyl)-2,3-dihydroxy-benzamidea) Methyl6-((E)-2-dimethylcarbamoyl-vinyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

A solution of methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate(130 mg, 0.32 mmol), N,N-dimethylacrylamide (47 mg, 0.47 mmol, 1.5 eq.),P(OPh)₃ (980 mg, 3.16 mmol, 10 eq.), Bu₄NBr (20 mg, 0.06 mmol, 0.2 eq.),Na₂CO₃ (40 mg, 0.38 mmol, 1.2 eq.) and Pd(OAc)₂ (10 mg, 0.03 mmol, 0.1eq.) in 10 mL dimethylacetamide was stirred at 140° C. for 72 h. Aftercooling to r.t. the mixture was partitioned between EtOAc and H₂O. Theorganic layer was washed twice with saturated NaCl solution, dried overMgSO₄ and evaporated in vacuo. The crude product was purified usingflash chromatography (silica gel, hexane/EtOAc 5:1→3:2) to yield thedesired compound as a colorless, slowly solidifying viscous oil.

Yield: 60 mg (44%). IR (KBr): 3059w; 2927w; 1721s; 1652s; 1607m; 1481m;1447s; 1396m; 1300m; 1256s; 1203s; 1046m; 1017m; 970w; 779w; 699m; 641w.¹H-NMR (300 MHz, CDCl₃): 3.11 (bs, 6 H, N(CH₃)₂); 3.96 (s, 3H, OCH₃);6.75 (d, J=15.6, 1H, C(O)CH); 7.20 (d, J=1.8, 1 H, H_(arom, Cat.));7.36-7.41 (m, 6 H, H_(arom, Ketal)); 7.55-7.61 (m, 6 H, H_(arom, Ketal),H_(arom, Cat.), Ar—CH). ¹³C-NMR (75 MHz, CDCl₃): 36.2; 37.7; 52.5;110.5; 113.0; 116.8; 119.1; 124.1; 126.6; 128.6; 129.6; 129.7; 139.6;141.5; 149.2; 149.5; 164.9; 166.7. HR-MS (MALDI): calcd. for C₂₆H₂₃NO₅Na([M+Na]⁺): 452.1474, found 452.1473.

b)6-((E)-2-Dimethylcarbamoyl-vinyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylicacid

Methyl6-((E)-2-dimethylcarbamoyl-vinyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylate(170 mg, 0.4 mmol, 1 eq.) and LiOH.H₂O (50 mg, 1.19 mmol, 3 eq.) werereacted according to GP3.

Yield: 126 mg (77%). Mp.: 230-231° C. IR (KBr): 3431w; 3058w; 1710s;1653m; 1596m; 1467m; 1445m; 1404w; 1249s; 1212m; 1176m; 1050m; 1027w;975w; 843w; 784w; 697w; 641w. ¹H-NMR (300 MHz, CDCl₃): 3.07 (s, 3 H,N(CH₃)₂); 3.16 (s, 3 H, N(CH₃)₂); 6.75 (d, J=15.3, 1H, C(O)CH); 7.24 (d,J=1.5, 1 H, H_(arom, Cat.)); 7.35-7.40 (m, 6 H, H_(arom, Ketal));7.59-7.62 (m, 5 H, H_(arom, Ketal.), Ar—CH); 7.67 (d, J=1.5, 1 H,H_(arom, Cat.)). ¹³C-NMR (75 MHz, CDCl₃): 36.1; 37.5; 110.6; 112.3;116.4; 119.2; 124.6; 126.3; 128.4; 129.4; 129.5; 139.2; 141.5; 149.1;149.8; 166.8; 167.8. HR-MS (MALDI): calcd. for C₂₅H₂₂NO₅ ([M+H]⁺):416.1498, found 416.1498.

c)6-((E)-2-Dimethylcarbamoyl-vinyl)-2,2-diphenyl-benzo[1,3]dioxole-4-carboxylicacid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

6-((E)-2-Dimethylcarbamoyl-vinyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylicacid (90 mg, 0.22 mmol, 1 eq.), EDC.HCl (63 mg, 0.33 mmol, 1.5 eq.),N-hydroxy-succinimide (33 mg, 0.28 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydro-furo[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(72 mg, 0.22 mmol, 1 eq.) and Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 63 mg (40%). Colorless foam. IR (KBr): 3424m; 2931w; 1653s;1598s; 1528m; 1474m; 1437m; 1374w; 1259m; 1207m; 1154w; 1081m; 1049m;1019m; 973w; 867w; 776w; 699w; 642w. ¹H-NMR (300 MHz, CDCl₃): 1.37 (s, 3H, CH_(3-exo)); 1.61 (s, 3 H, CH_(3-endo)); 3.05 (s, 3 H, N(CH₃)₂); 3.14(s, 3 H, N(CH₃)₂); 4.05 (m, 2 H, H—C(7′), H—C(7″)); 4.69 (m, 1 H,H—C(4′)); 4.96 (dd; J=6.6, 3.9, 1 H, H—C(3′)); 5.46 (dd, J=6.6, 2.1, 1H, H—C(2′)); 5.70 (bs, 2 H, NH₂); 5.84 (m, 2 H, H—C(5′), H—C(6′)); 6.08(d, J=2.1, 1 H, H—C(1′)); 6.82 (d, J=15.5, 1 H, C(O)CH); 7.07 (t, J=6.0,1 H, NHCO); 7.17 (d, J=1.7, 1 H, H_(arom, Cat.)); 7.35-7.42 (m, 6 H,H_(arom, Ketal)); 7.47-7.52 (m, 4 H, H_(arom, Ketal)); 7.60 (d, J=15.5,1 H, Ar—CH); 7.80 (d, J=1.7, 1 H, H_(arom, Cat.)); 7.84 (s, 1 H,H—C(8)); 8.19 (s, 1 H, H—C(2)). ¹³C-NMR (75 MHz, CDCl₃): 25.4; 27.1;35.9; 37.4; 40.7; 84.1; 84.5; 87.2; 90.3; 110.6; 114.6; 115.4; 117.0;119.2; 120.2; 122.8; 126.4; 128.5; 129.8; 130.3; 130.5; 138.5; 138.6;139.8; 141.2; 145.6; 147.9; 149.4; 153.0; 155.3; 162.9; 166.5. HR-MS(MALDI): calcd. for C₄₀H₄₀N₇O₇ ([M+H]⁺): 730.2989, found 730.2993.

d)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]prop-2-enyl}-5-((E)-2-dimethylcarbamoyl-vinyl)-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (35 mg, 0.048 mmol) affordedthe desired product as a colorless solid.

Yield: 12 mg (48%). t_(R,analyt.): 9.7 min. IR (KBr): 3373 br, s; 1696s;1642s; 1591s; 1499w; 1419w; 1307w; 1264w; 1201m; 1138w; 1052w; 977w;840w; 800w; 723w; 642w. ¹H-NMR (500 MHz, ): 3.05 (s, 3 H, N(CH₃)₂); 3.22(s, 3 H, N(CH₃)₂); 4.07 (m, 2 H, H—C(7′), H—C(7″)); 4.24 (t, J=5.0, 1 H,H—C(4′)); 4.53 (m, 1 H, H—C(3′)); 4.74 (t, J=4.8, 1 H, H—C(2′)); 5.95(m, 2 H, H—C(5′), H—C(6′)); 6.06 (d, J=4.8, H—C(1′)); 6.96 (d, J=15.4, 1H, C(O)CH); 7.25 (d, J=1.8, 1 H, H_(arom, Cat.)); 7.46 (d, J=15.4, 1 H,Ar—CH); 7.53 (d, J=1.8, 1 H, H_(arom, Cat.)); 8.26 (s, 1 H, H—C(8));8.40 (s, 1 H, H—C(2)). ¹³C-NMR (125 MHz,): 36.3; 37.9; 41.7; 75.3; 75.8;86.2; 90.7; 116.5; 116.6; 117.9; 199.9; 120.8; 127.5; 130.4; 131.0;143.5; 143.6; 147.5; 148.0; 150.2; 152.4; 153.3; 169.3; 171.0. HR-MS(MALDI): calcd. for C₂₄H₂₇N₇O₇Na ([M+Na]⁺): 548.1864, found 548.1859.

EXAMPLE 16 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-trifluoromethyl-2,3-dihydroxy-benzamidea) 2-Methoxymethoxy-5-trifluoromethyl-phenol

To a solution of 1-methoxymethoxy-4-trifluoromethyl-benzene (4.6 g,22.31 mmol) in 60 mL dry THF cooled to −78° C., BuLi (21 mL of a 1.6 msol. in hexane, 1.5 eq.) was added drop-wise via a syringe and themixture was stirred at low temperature for 2 h, then the cooling bathwas removed and the mixture was allowed to gradually warm to 0° C.during 30 min. After cooling again to −78° C., B(OCH₃)₃ (3.95 g, 38mmol, 1.7 eq.) was added to the reaction and the stirring was continuedfor another 1.5 h at −78° C., then the solution was allowed to warm to−10° C. during 20 min. Re-cooling to −78° C. was followed by addition ofH₂O₂ (5.82 mL of a 30% solution in H₂O, 2 eq.) and NaOH_(aq) (5.8 mL ofa 5 m aqueous solution, 1.3 eq.). This solution was stirred 16 h atr.t., then saturated NH₄Cl-solution was added and the mixture wasextracted twice with 30 mL EtOAc. The pooled organic fractions werewashed with saturated NaCl solution, dried over MgSO₄ and evaporated invacuo. The crude product was purified using flash chromatography (silicagel, hexane/EtOAc 4:1) to yield the desired product as a yellowish oil.

Yield: 3.5 g (70%). IR (neat): 3426br, m; 2962m; 1709w; 1622m; 1516s;1464m; 1330s; 1290s; 1162s; 1123s; 1085s; 982s; 914s; 879m; 816m; 762w;658w; 618w. ¹H-NMR (300 MHz, CDCl₃): 3.52 (s, 3 H, OCH₃); 5.26 (s, 2H,OCH₂O); 5.97 (s, 1H, OH); 7.10-7.20 (m, 3 H, H_(arom)). ¹³C-NMR (75 MHz,CDCl₃): 56.6; 95.5; 112.4 (d, J=3.6); 114.7; 117.5 (d, J=3.6); 120.3 (q,J=260); 125.0 (q, J=32.8); 146.1; 146.7. ¹⁹F-NMR (282 MHz, CDCl₃): −62.4(s). HR-MS (EI+): calcd. for C₉H₉F₃O₃ ([M]⁺): 222.0504, found 222.0501.

b) 3-Bromo-5-trifluoromethyl-benzene-1,2-diol

To a solution of 4-trifluoromethyl-benzene-1,2-diol (870 mg, 4.8 mmol)in 20 mL CCl₄, Br₂ (770 mg, 4.8 mmol, 1 eq.) was added and the mixturewas stirred at 60° C. for 10 h. The sol-vent was then removed in vacuoand the crude product was purified by flash chromatography (silica gel,hexane/EtOAc 4:1→3:2) to yield the desired product as a yellowish oil.

Yield: 910 mg (74%). ¹H-NMR (300 MHz, CDCl₃): 5.68 (bs, 1H, OH); 5.81(bs, 1H, OH); 7.14 (dd, J=2.3, 0.6, 1 H, H_(arom)); 7.32 (dd, J=2.3,0.6, 1 H, H_(arom)).

c) 1,2-Bis-benzyloxy-3-bromo-5-trifluoromethyl-benzene

To a solution of 3-bromo-5-trifluoromethyl-benzene-1,2-diol (510 mg,1.98 mmol) in 10 mL acetone, K₂CO₃ (2.74 g, 19.84 mmol, 10 eq.) andbenzyl bromide (1.02 g, 5.95 mmol, 3 eq.) were added and the solutionwas refluxed for 4 h. After cooling to r.t., H₂O and EtOAc were added tothe mixture and the phases were separated The organic fraction waswashed with saturated NaCl solution, dried over MgSO₄ and evaporated invacuo. The crude product was purified using flash chromatography (silicagel, hexane/EtOAc 10:1) to yield the title compound as a colorlesssolid.

Yield: 750 mg (87%). Mp.: 79-80° C. IR (KBr): 3032w; 2935w; 2884w;1576w; 1499w; 1485w; 1455w; 1424m; 1382w; 1335s; 1290m; 1230m; 1164s;1120s; 1011m; 957m; 919w; 859w; 751m; 698m. ¹H-NMR (300 MHz, CDCl₃):5.09 (s, 2 H, OCH₂Ar); 5.15 (s, 2 H, OCH₂Ar); 5.97 (s, 1H, OH); 7.18 (d,J=1.5, 1 H, H_(arom, Cat.)); 7.32-7.47 (m, 11 H, H_(arom, Cat.),H_(arom, Benzyl.)). ¹³C-NMR (75 MHz, CDCl₃): 71.5; 75.0; 110.3 (d,J=3.9); 118.4; 122.5 (d, J=3.9); 123.1 (q, J=271); 127.0 (q, J=33.6);127.6; 128.2; 128.3; 128.4; 128.5; 128.6; 135.5; 136.3; 148.4; 152.8.¹⁹F-NMR (282 MHz, CDCl₃): −62.6 (s). HR-MS (MALDI): calcd. forC₂₁H₁₆BrF₃O₂Na ([M+Na]⁺): 459.0183, found 459.0169.

d) Methyl 2,3-bis-benzyloxy-5-trifluoromethyl-benzoate

To a solution of 1,2-bis-benzyloxy-3-bromo-5-trifluoromethyl-benzene(750 mg, 1.76 mmol) in 10 mL dry THF cooled to −90° C., BuLi (3.3 mL ofa 1.6 m solution in hexane, 5.28 mmol, 3 eq.) was slowly added via asyringe and the yellow solution was stirred at low temperature for 15min. Methyl chloroformate (1.66 g, 17.6 mmol, 10 eq.) was then added tothe solution and the reaction mixture was allowed to warm to r.t. wherethe stirring was continued for 1 h. The mixture was then poured into aseparatory funnel containing H₂O and EtOAc and the phases wereseparated. The organic phase was washed with brine, dried over MgSO₄ andevaporated in vacuo. The crude product was purified using flashchromatography (silica gel, hexane/EtOAc 10:1) to yield the desiredcompound as a colorless solid.

Yield: 383 mg (52%). Mp.: 78-79° C. IR (KBr): 3033w; 2950w; 1733s;1610w; 1486w; 1430m; 1363s; 1299m; 1250s; 1199m; 1151m; 1121s; 1045s;956w; 935w; 909w; 867w; 750w; 698m. ¹H-NMR (300 MHz, CDCl₃): 3.87 (s,3H, OCH₃); 5.14 (s, 2 H, OCH₂Ar); 5.17 (s, 2 H, OCH₂Ar); 7.30-7.45 (m,11 H, H_(arom, Cat.), H_(arom, Benzyl.)); 7.65 (dd, J=1.8, 1.2, 1 H,H_(arom, Cat.)). ¹³C-NMR (75 MHz, CDCl₃): 52.5; 71.6; 75.8; 113.9 (d,J=3.3); 118.0; 119.9 (d, J=3.3); 123.4 (q, J=270); 126.0 (q, J=33.6);127.0; 127.6; 128.1; 128.3; 128.4; 128.5; 128.6; 135.5; 136.6; 150.7;153.0; 165.4. ¹⁹F-NMR (282 MHz, CDCl₃): −62.7 (s). HR-MS (MALDI): calcd.for C₂₃H₁₉F₃O₂Na ([M+Na]⁺): 439.1133, found 439.1132. Anal. calcd. forQ₃H₁₉O₄F₃: C, 66.34, H 4.60. found C 66.16, H 4.78.

e) Methyl 2,3-dihydroxy-5-trifluoromethyl-benzoate

To a solution of methyl 2,3-bis-benzyloxy-5-trifluoromethyl-benzoate(280 mg, 0.67 mmol) in 10 mL MeOH, Pd/C (10%, 30 mg) was added and themixture was stirred 16 h under a H₂ atmosphere. The reaction mixture wasthen filtered through Celite and evaporated in vacuo to yield the titlecompound as a greyish solid.

Yield: 148 mg (99%). IR (KBr): 3462m; 3132w; 2961w; 1676m; 1494m; 1447m;1338s; 1245s; 1199m; 1120s; 1014w; 936w; 887w; 793m; 679m. ¹H-NMR (300MHz, CD₃OD): 3.97 (s, 3H, OCH₃); 7.17 (s, 1 H, H_(arom, Cat)); 7.58 (s,1 H, H_(arom, Cat)). ¹³C-NMR (75 MHz, CD₃OD): 53.2; 113.6; 116.9; 118.0;121.8 (q, J=32.8); 125.3 (q, J=268); 148.6; 154.6; 170.9. ¹⁹F-NMR (282MHz, CD₃OD): −62.0 (s). HR-MS (MALDI): calcd. for C₈H₃F₃O₃ ([M-CH₃OH]⁺):204.0034, found 204.0024.

f) Methyl2,2-Bis-(4-methoxy-phenyl)-6-trifluoromethyl-1,3-benzodioxole-4-carboxylate

4,4′-Dimethoxybenzophenone (213 mg, 0.88 mmol, 1.5 eq.), oxalyl chloride(900 mg, 7.1 mmol, 8 eq.) and methyl2,3-dihydroxy-5-trifluoromethyl-benzoate (130 mg, 0.59 mmol, 1 eq.) werereacted according to GP2.2. The crude product was purified using flashchromato-graphy (silica gel, hexane/Et₂O 10:1) to yield the titlecompound as a yellowish, very viscous oil.

Yield: 170 mg (63%). IR (neat): 3003w; 2956w; 2839w; 1727s; 1642w;1612s; 1585w; 1514s; 1486m; 1445s; 1324s; 1268s; 1234s; 1175s; 1123m;1042s; 1005m; 935w; 832m; 783w; 674w. ¹H-NMR (300 MHz, CDCl₃): 3.81 (s,6H, ArOCH₃); 3.95 (s, 3H, C(O)OCH₃); 6.90 (dd, J=6.7, 2.3, 4 H,H_(arom, Ketal)); 7.74 (d, J=1.5, 1 H, H_(arom, Cat.)). ¹³C-NMR (75 MHz,CDCl₃): 52.4; 55.4; 108.6 (d, J=3.1); 112.3; 113.7; 120.2; 120.8 (d,J=4.3); 123.5 (q, J=270); 123.6 (q, J=33.4); 128.0; 131.0; 148.9; 150.7;160.4; 163.8. ¹⁹F-NMR (282 MHz, CDCl₃): −61.8 (s). HR-MS (MAIDI): calcd.for C₂₄H₂₀F₃O₆ ([M+H]⁺): 461.1212, found 461.1202. Anal. calcd. forC₂₄H₁₉O₆F₃: C, 62.61, H 4.16. found C 62.52, H 4.26.

g)2,2-Bis-(4-methoxy-phenyl)-6-trifluoromethyl-1,3-benzodioxole-4-carboxylicacid

Methyl2,2-bis-(4-methoxy-phenyl)-6-trifluoromethyl-1,3-benzodioxole-4-carboxylate(60 mg, 0.13 mmol, 1 eq.) and LiOH.H₂O (28 mg, 0.65 mmol, 5 eq.) werereacted according to GP3.

Yield: 53 mg (91%). Mp.:. IR (KBr): 3441br, w; 2936w; 2837w; 1687w;1611s; 1513s; 1442m; 1364m; 1312s; 1253s; 1175s; 1121m; 1031s; 1005m;952w; 931w; 831m; 676w. ¹H-NMR (300 MHz, CDCl₃): 3.79 (s, 6H, ArOCH₃);6.94 (dd, J=6.9, 2.1, 4 H, H_(arom, Ketal)); 7.30 (d, J=1.5, 1 H,H_(arom, Cat)); 7.46 (dd, J=6.9, 2.1, 4 H, H_(arom, Ketal)); 7.70 (d,J=1.5, 1 H, H_(arom, Cat.)) ¹⁹F-NMR (282 MHz, CDCl₃): −63.7 (s). HR-MS(MALDI): calcd. for C₂₄H₂₀F₃O₆ ([M+H]⁺): 447.1055, found 447.1059.

h)2,2-Bis-(4-methoxy-phenyl)-6-trifluoromethyl-benzo[1,3]dioxole-4-carboxylicacid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-Bis-(4-methoxy-phenyl)-6-trifluoromethyl-1,3-benzodioxole-4-carboxylicacid (90 mg, 0.2 mmol, 1 eq.), EDC.HCl (58 mg, 0.3 mmol, 1.5 eq.),N-hydroxy-succinimide (31 mg, 0.26 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(70 mg, 0.2 mmol, 1 eq.) and Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 119 mg (77%). Colorless foam. Mp.: 114-118° C. IR (KBr): 3426m;3178w; 2935w; 2837w; 1640s; 1607s; 1514m; 1443w; 1375w; 1317s; 1254s;1210m; 1175s; 1121m; 1025m; 1004w; 867w; 732m. ¹H-NMR (300 MHz, CDCl₃):1.38 (s, 3 H, CH_(3-exo)); 1.62 (s, 3 H, CH_(3-endo)); 3.81 (s, 6 H,OCH₃); 4.04 (m, 2 H, H—C(7′), H—C(7″)); 4.68 (m, 1 H, H—C(4′)); 4.95(dd; J=6.6, 3.6, 1 H, H—C(3′)); 5.45 (dd, J=6.6, 2.1, 1 H, H—C(2′));5.81 (m, 4 H, H—C(5′), H—C(6′), NH₂); 6.08 (d, J=2.1, 1 H, H—C(1′));6.88-6.92 (m, 4 H, H_(arom, Ketal)); 7.09 (t, J=5.7, 1 H, NHCO); 7.19(d, J=2.1, 1 H, H_(arom, Cat.)); 7.36-7.42 (m, 4H, H_(arom, Ketal));7.85 (s, 1 H, H—C(8)); 7.91 (d, J=2.1, 1 H, H_(arom, Cat.)); 8.22 (s, 1H, H—C(2)). ¹³C-NMR (75 MHz, CDCl₃): 25.4; 27.2; 40.9; 55.4; 84.1; 84.5;87.1; 90.2; 108.3; 113.7; 114.6; 115.1; 120.1; 120.6; 120.7; 123.54 (q,J=270); 124.6 (q, J=33.5); 128.1; 128.5; 130.1; 130.3; 139.8; 147.2;147.9; 149.2; 152.3; 155.1; 160.7; 162.0. ¹⁹F-NMR (282 MHz, CDCl₃):−61.7 (s). HR-MS (MALDI): calcd. for C₃₈H₃₆F₃N₆O₈ ([M+H]⁺): 761.2547,found 759.2535.

i)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-trifluoromethyl-2,3-dihydroxybenzamide

GP8, starting from the protected precursor (75 mg, 0.1 mmol) affordedthe desired product as a colorless solid.

Yield: 48 mg (99%). t_(R, analyt.): 14.7 min. IR (KBr): 3409 br, s;1670s; 1649m; 1607m; 1545w; 1398w; 1327m; 1194m; 1124m; 1049w; 801w;725w. ¹H-NMR (500 MHz, ): 4.06 (m, 2 H, H—C(7′), H—C(7″)); 4.24 (t,J=5.1, 1 H, H—C(4′)); 4.52 (m, 1 H, H—C(3′)); 4.71 (t, J=4.8, 1 H,H—C(2′)); 5.95 (m, 2 H, H—C(5′), H—C(6′)); 6.06 (d, J=4.8, H—C(1′));7.15 (d, J=1.2, 1 H, H_(arom, Cat.)); 7.64 (d, J=1.2, 1 H,H_(arom, Cat.)); 8.29 (s, 1 H, H—C(8)); 8.39 (s, 1 H, H—C(2)). ¹³C-NMR(125 MHz, ):41.8; 75.3; 75.6; 86.1; 90.6; 115.5 (q, J=2.5); 116.4 (q,J=5.0); 116.9; 120.8; 121.9 (q, J=32.5); 125.7 (q, J=269); 130.5; 130.9;143.4; 147.8; 148.3; 150.3; 153.3; 153.6; 170.1. ¹⁹F-NMR (282 MHz,CDCl₃): −61.6 (s). HR-MS (MALDI): calcd. for C₂₀H₂₀F₃N₆O₆ ([M+H]⁺):497.1396, found 497.1401.

EXAMPLE 17 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-isopropyl-2,3-dihydroxy-benzamidea) 4-Isopropenyl-2-methoxy-1-methoxymethoxy-benzene

A suspension of methyltriphenylphosphonium bromide (1.1 g, 3.09 mmol,1.3 eq.) in 5 mL dry THF cooled to −80° C. was slowly treated with BuLi(1.94 mL of a 1.6 m solution in hexane, 1.3 eq.). To this yellowsuspension a solution of 1-(3-methoxy-4-methoxymethoxy-phenyl)-ethanone(500 mg, 2.38 mmol, 1 eq.) in 5 mL dry THF was added and the reactionmixture was allowed to warm to r.t. where stirring was continued for 12h. The suspension was filtered and the solvent was evaporated in vacuo.The crude product was purified using flash chromatography (silica gel,hexane/EtOAc 6:1) to yield the desired product as a color-less oil.

Yield: 424 mg (86%). IR (neat): 3085w; 2952m; 2827w; 1627w; 1602w;1580m; 1513s; 1463m; 1413m; 1300m; 1248s; 1224m; 1157s; 1139s; 1077s;997s; 922m; 885m; 817w; 765w. ¹H-NMR (300 MHz, CDCl₃): 2.14 (s, 3 H,CH₃); 3.52 (s, 3 H, Ar—OCH₃); 3.91 (s, 3 H, OCH₃); 5.03 (qu, J=1.5, 1 H,CH₂); 5.23 (s, 2 H, OCH₂O); 5.29 (qu, J=1.5, 1 H, CH₂); 6.98-7.03 (m, 2H, H_(arom)); 7.11 (d, J=8.4; 1 H, H_(arom)). ¹³C-NMR (75 MHz, CDCl₃):21.9; 55.8; 56.2; 95.4; 109.2; 111.4; 115.9; 118.1; 135.9; 142.9; 146.0;149.3. HR-MS (EI+): calcd. for C₁₂H₁₆O₃ ([M]⁺): 208.1099, found208.1097.

b) 4-Isopropyl-2-methoxy-1-methoxymethoxy-benzene

To a solution of 4-isopropenyl-2-methoxy-1-methoxymethoxy-benzene (3.5g, 16.81 mmol) in 20 mL MeOH, Pd/C (10%, 350 mg) was added and themixture was stirred 16 h under a H₂ atmosphere. The reaction mixture wasthen filtered through Celite and evaporated in vacuo and briefly driedunder vacuum to yield the title compound as a colorless oil.

Yield: 3.31 g (94%). IR (neat): 2959s; 2827w; 1592w; 1516s; 1464s;1419m; 1297w; 1266s; 1228s; 1198m; 1156s; 1079s; 1037w; 1004s; 923m;852w; 815w; 763w; 653w. ¹H-NMR (300 MHz, CDCl₃): 1.24 (d, J=7.0, 6 H,CH₃); 2.86 (sep, J=7.0, 1 H, CH); 3.52 (s, 3 H, Ar—OCH₃); 3.88 (s, 3 H,OCH₃); 5.20 (s, 2 H, OCH₂O); 6.73-6.78 (m, 2 H, H_(arom)); 7.07 (d,J=8.1; 1 H, H_(arom)). ¹³C-NMR (75 MHz, CDCl₃): 24.1; 33.8; 55.8; 56.1;95.6; 110.3; 116.5; 118.2; 143.5; 144.4; 149.5. HR-MS (EI+): calcd. forC₁₂H₁₈O₃ ([M]⁺): 210.1256, found 210.1246.

c) Methyl 5-Isopropyl-3-methoxy-2-methoxymethoxy-benzoate

To a solution of 4-isopropyl-2-methoxy-1-methoxymethoxy-benzene (2.0 g,9.51 mmol) in 35 mL dry THF cooled to 0° C., BuLi (9 mL of a 1.6 msolution in hexane, 1.5 eq.) was added dropwise via a syringe and thereaction mixture was stirred 2.5 h at 0° C. This solution was thenslowly added to a solution of methyl chloroformate (9 g, 95.1 mmol, 10eq.) in 10 mL dry THF at 0° C. The mixture was stirred 12 h at r.t.Saturated KHCO₃ solution and EtOAc were then added to the solution andthe phases were separated. The organic layer was washed twice withsaturated NaCl solution, dried over MgSO₄ and evaporated in vacuo. Thecrude product was purified using flash chromatography (silica gel,hexane EtOAc 9:1→6:1) to yield the title compound as a yellowish oil.

Yield: 1.3 g (51%). IR (neat): 2960m; 2841w; 1769m; 1729s; 1586w; 1487m;1464m; 1439m; 1339m; 1263s; 1207s; 1157m; 1063s; 961s; 860w; 797w; 656w.¹H-NMR (300 MHz, CDCl₃); 1.24 (d, J=6.9, 6 H, CH₃); 2.88 (sep, J=6.9, 1H, CH); 3.57 (s, 3 H, Ar—OCH₃); 3.86 (s, 3 H, OCH₃); 3.90 (s, 3 H,C(O)OCH₃); 5.10 (s, 2 H, OCH₂O); 6.91 (d, J=2.1, 1 H, H_(arom)); 7.18(d, J=2.1; 1 H, H_(arom)). ¹³C-NMR (75 MHz, CDCl₃): 24.0; 34.0; 52.2;56.2; 75.4; 99.4; 114.4; 119.8; 126.0; 143.3; 144.9; 152.8; 166.8. HR-MS(EI+): calcd. for C₁₄H₂₀O₅ ([M]⁺): 268.1311, found 268.1300.

d) 2,3-Dihydroxy-5-isopropyl-benzoic acid

To a solution of methyl 5-Isopropyl-3-methoxy-2-methoxymethoxy-benzoatein 5 mL dry CH₂Cl₂ cooled to −80° C., BBr₃ (3.4 mL of a 1 m solution inCH₂Cl₂) was added dropwise via a syringe. The mixture was then stirred30 min. at −70° C., then the cooling bath was removed and the stirringcontinued at r.t. for 1 h. The reaction was the quenched by addition ofH₂O and the resulting mixture was extracted twice with 30 mL CH₂Cl₂. Thecombined organic fractions were dried over MgSO₄ and evaporated in vacuoto yield a brown solid. This material was redissolved in 1 mL AcOH towhich 2.5 mL HBr (33% in AcOH) was added The mixture was stirred at 120°C. for 5 h, then H₂O was slowly added and the mixture was extracted withEtOAc. The organic layer was washed twice with saturated NaCl solution,dried over MgSO4 and evaporated in vacuo to yield the desired product asa brown solid.

Yield: 45 mg (41%). Mp.: 151-152° C. IR (KBr): 3311m; 2958s; 1675s;1613w; 1483s; 1384w; 1276s; 1161s; 986w; 872w; 796w; 778w; 728w; 703w.¹H-NMR (300 MHz, CDCl₃): 1.22 (d, J=7.1, 6 H, CH₃); 2.84 (sep, J=7.1, 1H, CH); 5.64 (bs, 1 H, OH); 7.09 (d, J=2.4, 1 H, H_(arom)); 7.30 (d,J=2.4; 1 H, H_(arom)); 10.29 (s, 1 H, OH). ¹³C-NMR (75 MHz, CDCl₃):23.9; 33.5; 110.8; 118.7; 119.7; 140.5; 144.8; 147.4; 174.8. HR-MS(EI+): calcd. for C₁₀H₁₀O₃ ([M−H₂O]⁺): 278.0630, found 278.0623.

e) Methyl 2,3-dihydroxy-5-isopropyl-benzoate

2,3-Dihydroxy-5-isopropyl-benzoic acid (140 mg, 0.71 mmol, 1 eq.) andSOCl₂ (430 mg, 3.6 mmol, 5 eq.) were reacted according to GP1.

Yield: 125 mg (83%). Grayish solid. Mp.: 66-67° C. IR (KBr): 3425s;2955m; 1688s; 1485s; 1438s; 1338s; 1276s; 1231m; 1159m; 1112w; 1018m;964w; 893w; 785m; 693w; 641w. ¹H-NMR (300 MHz, CDCl₃): 1.21 (d, J=6.9, 6H, CH₃); 2.82 (sep, J=6.9, 1 H, CH); 3.95 (s, 3 H, OCH₃); 5.61 (s, 1 H,OH); 7.02 (d, J=2.0, 1 H, H_(arom)); 7.21 (d, J=2.0, 1 H, H_(arom));10.69 (s, 1 H, OH). ¹³C-NMR (75 MHz, CDCl₃): 23.9; 33.5; 52.3; 111.8;117.7; 118.4; 140.1; 144.7; 146.9; 170.8. HR-MS (EI+): calcd. forC₁₁H₁₄O₄ ([M]⁺): 210.0892, found 210.0892.

f) Methyl 6-isopropyl-2,2-diphenyl-1,3-benzodioxole-4-carboxylate

Methyl 2,3-dihydroxy-5-isopropyl-benzoate (85 mg, 0.4 mmol, 1 eq.) anddichlorodiphenyl-methane (125 mg, 0.53 mmol, 1.3 eq.) were reactedaccording to GP2, Method B.

Yield: 112 mg (74%). Colorless solid. Mp.: 108-110° C. IR (KBr): 2959w;1714s; 1478s; 1447s; 1385w; 1285m; 1045m; 1017m; 915w; 868w; 807m; 782m;701s; 641m. ¹H-NMR (300 MHz, CDCl₃): 1.21 (d, J=6.8, 6 H, CH₃); 2.85(sep, J=6.8, 1 H, CH); 3.94 (s, 3 H, OCH₃); 6.92 (d, J=1.9, 1 H,H_(arom, Cat.)); 7.26 (d, J=1.9, 1 H, H_(arom)); 7.35-7.41 (m, 6 H,H_(arom, Ketal)); 7.60-7.65 (m, 4 H, H_(arom, Ketal)). ¹³C-NMR (75 MHz,CDCl₃): 24.0; 33.9; 52.0; 111.0; 112.1; 117.7; 119.9; 126.4; 128.2;129.2; 140.0; 142.5; 146.3; 148.3; 165.4. HR-MS (MALDI): calcd. forC₂₄H₂₂O₄Na ([M+Na]⁺): 397.1416, found 397.1414.

g) 6-Isopropyl-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid

Methyl 6-isopropyl-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (100 mg,0.267 mmol, 1 eq.) and LiOH.H₂O (45 mg, 1.07 mmol, 4 eq.) were reactedaccording to GP3.

Yield: 91 mg (95%). Colorless solid. IR (KBr): 2958m; 2630w; 1683s;1478s; 1450s; 1254s; 1207s; 1044m; 1023m; 947w; 864w; 760w; 697m; 641w.¹H-NMR (300 MHz, CDCl₃): 1.21 (d, J=6.9, 6 H, CH₃); 2.86 (sep, J=6.9, 1H, CH); 6.97 (d, J=1.8, 1 H, H_(arom, Cat.)); 7.31 (d, J=1.8, 1 H,H_(arom)); 7.35-7.42 (m, 6 H, H_(arom, Ketal)); 7.61-7.64 (m, 4 H,H_(arom, Ketal)). ¹³C-NMR 75 MHz, CDCl₃): 24.0; 33.8; 111.2; 111.9;118.2; 120.3; 126.4; 128.3; 129.3; 139.8; 142.7; 146.9; 148.4; 169.6.HR-MS (MALDI): calcd. for C₂₃H₂₀O₄Na ([M+Na]⁺): 383.1259, found383.1250.

h) 2,2-Diphenyl-6-isopropyl-benzo[1,3]dioxole-4-carboxylic acid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

6-Isopropyl-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (80 mg, 0.22mmol, 1 eq.), EDC.HCl (64 mg, 0.33 mmol, 1.5 eq.), N-hydroxy-succinimide(34 mg, 0.29 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydrofuro[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(81 mg, 0.24 mmol, 1.1 eq.) and Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 89 mg (57%). Colorless foam. IR (KBr): 3424m; 3179w; 2960w;1645s; 1598s; 1530m; 1475s; 1449m; 1330w; 1255s; 1208s; 1156w; 1081m;1047m; 1018m; 949w; 867w; 779w; 699w; 642w. ¹H-NMR (300 MHz, CDCl₃):1.21 (d, J=6.9, 6 H, CH₃); 1.37 (s, 3 H, CH_(3-exo)); 1.62 (s, 3 H,CH_(3-endo)); 2.88 (sep, J=6.9, 1 H, CH); 4.05 (m, 2 H, H—C(7′),H—C(7″)); 4.68 (m, 1 H, H—C(4″)); 4.93 (dd; J=6.6, 3.9, 1 H, H—C(3′));5.44 (dd, J=6.6, 2.4, 1 H, H—C(2′)); 5.79 (bs, 2 H, NH₂); 5.86 (m, 2 H,H—C(5′), H—C(6′)); 6.08 (d, J=2.4, 1 H, H—C(1′)); 6.92 (d, J=1.5, 1 H,H_(arom, Cat.)); 7.14 (t, J=5.4, 1 H, NHCO); 7.35-7.39 (m, 6 H,H_(arom, Ketal)); 7.43 (d, J=1.5, 1 H, H_(arom, Cat.)); 7.48-7.53 (m, 4H, H_(arom, Ketal)); 7.86 (s, 1 H, H—C(8)); 8.23 (s, 1 H, H—C(2)).¹³C-NMR (75 MHz, CDCl₃): 24.1; 25.5; 27.2; 34.1; 40.7; 84.0; 84.4; 87.0;90.1; 110.3; 114.7; 118.0; 119.7; 120.1; 126.3; 128.0; 128.3; 128.4;129.5; 130.8; 139.1; 139.8; 142.7; 143.4; 147.1; 149.3; 152.5; 155.0;163.5. HR-MS (MALDI): calcd. for C₃₈H₃₉N₆O₆ ([M+H]⁺): 675.2931, found675.2947.

i)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-isopropyl-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (50 mg, 0.074 mmol) affordedthe desired product as a grayish solid.

Yield: 29 mg (85%). t_(R, analyt.): 12.2 min. IR (KBr): 3378br, s;2962m; 1700s; 1641m; 1594m; 1542m; 1484w; 1430w; 1323w; 1201s; 1137m;1049w; 970w; 836w; 800w; 724w; 642w. ¹H-NMR (500 MHz, CD₃OD): 1.21 (d,J=6.8, 6 H, CH₃); 2.79 (sep, J=6.8, 1 H, CH); 4.03 (m, 2 H, H—C(7′),H—C(7″)); 4.23 (t, J=4.9, 1 H, H—C(4+)); 4.51 (m, 1 H, H—C(3′)); 4.73(t, J=4.8, 1 H, H—C(2′)); 5.94 (m, 2 H, H—C(5′), H—C(6′)); 6.03 (d,J=4.8, H—C(1′)); 6.85 (d, J=2.0, 1 H, H_(arom, Cat.)); 7.12 (d, J=2.0, 1H, H_(arom, Cat.)); 8.22 (s, 1 H, H—C(8)); 8.37 (s, 1 H, H—C(2)).¹³C-NMR (125 MHz, CD₃OD): 24.5; 35.0; 41.6; 75.2; 75.6; 86.1; 90.6;116.2; 116.3; 118.2; 120.8; 130.2; 131.2; 140.7; 143.2; 147.1; 148.2;148.7; 150.3; 154.1; 171.5. HR-MS (MALDI): calcd. for C₂₂H₂₇N₆O₆([M+H]⁺): 471.1992, found 471.1981.

EXAMPLE 18 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-ylprop-2-enyl}-5-(toluene-4-sulfonyl)-2,3-dihydroxy-benzamide a) Methyl2,3-dimethoxy-5-(toluene-4-sulfonyl)-benzoate

To a solution of methyl 5-iodo-2,3-dimethoxy-benzoate (2.25 g, 7.0 mmol)in 20 mL DMF, sodium p-toluenesulfinate hydrate (2.21 g, 11.26 mmol, 1.6eq.) and CuI (2.22 g, 11.6 mmol, 1.66 eq.) were added and light greensolution was stirred at 110° C. for 14 h. H₂O and EtOAc were then addedto the mixture and the phases were separated. The organic layer waswashed with saturated NaCl solution, dried over MgSO₄ and evaporatedunder reduced pressure. The crude product was purified using flashchromatography (silica gel, hexane/EtOAc 8:2→3:2) to yield the desiredproduct as a colorless solid.

Yield. 1.41 g (58%). Mp.: 114° C. IR (KBr): 3081w; 2945w; 1731s; 1594w;1482m; 1426w; 1317s; 1273s; 1146s; 1104m; 994w; 872w; 811w; 713w; 665m;585m; 535w. ¹H-NMR (300 MHz, CDCl₃): 2.40 (s, 3 H, ArCH₃); 3.90 (s, 3 H,ArOCH₃); 3.92 (s, 3 H, ArOCH₃); 3.92 (s, 3 H, C(O)OCH₃); 7.31 (d, J=8.1,2 H, H_(arom, p-Tol.)); 7.54 (d, J=2.1, 1 H, H_(arom, Cat.)); 7.82 (d,J=8.1, 2 H, H_(arom, p-Tol).); 7.87 (d, J=2.1; 1 H, H_(arom, Cat.)).¹³C-NMR (75 MHz, CDCl₃): 21.7; 52.6; 56.5; 61.7; 113.4; 122.0; 126.4;127.5; 129.9; 136.8; 138.2; 144.2; 152.7; 153.8; 164.9. HR-MS (MALDI):calcd. for C₁₇H₁₈O₆SNa ([M+Na]⁺): 373.0722, found 373.0714. Anal. calcd.for C₁₇H₁₈O₆S: C 58.27, H 5.18. found C 58.38, H 5.36.

b) 2,3-Dihydroxy-5-(toluene-4-sulfonyl)-benzoic acid

Methyl 2,3-dimethoxy-5-(toluene-4-sulfonyl)-benzoate (1.3 g, 4.036 mmol)was dissolved in 5 mL AcOH to which HBr (15 mL of a 33% solution inAcOH) and Bu₄NBr (1.1 g, 3.4 mmol, 0.85 eq.) were added. The reactionmixture was stirred at 140° C. for 20 h, then H₂O was slowly added andthe mixture was extracted with EtOAc. The organic layer was washed twicewith saturated NaCl solution, dried over MgSO₄ and evaporated in vacuo.The crude product was purified using flash chromatography (silica gel,hexane/EtOAc/AcOH 3:2:0.2→1:3:0.2) to yield the desired product as anorange solid.

Yield: 560 mg (45%). Mp.: 223-225° C. (dec.). IR (KBr): 3165br, m;1692m; 1597w; 1467m; 1403w; 1282s; 1214w; 1141s; 1094m; 967w; 893w;799w; 743w; 709m; 665m. ¹H-NMR (300 MHz, DMSO-d₆): 2.35 (s, 3 H, ArCH₃);4.42 (bs, 1 H, OH); 7.28 (d, J=2.1, 1 H, H_(arom, Cat.)); 7.39 (d,J=8.1, 2 H, H_(arom, p-Tol.)); 7.75 (m, 3 H, H_(arom, Cat.),H_(arom, p-Tol.)); 9.86 (bs, 1 H, OH). ¹³C-NMR (75 MHz, DMSO-d₆): 21.0;114.7; 115.6; 120.0; 126.8; 128.7; 130.0; 138.9; 143.6; 147.1; 156.4;170.5. HR-MS (MALDI): calcd. for C₁₄H12O₆SNa ([M+Na]⁺): 331.0252, found331.0246.

c) Methyl 2,3-dihydroxy-5-(toluene-4-sulfonyl)-benzoate

2,3-Dihydroxy-5-(toluene-4-sulfonyl)-benzoic acid (410 mg, 1.33 mmol, 1eq.) and SOCl₂ (790 mg, 6.65 mmol, 5 eq.) were reacted according to GP1.

Yield: 321 mg (75%). Orange solid. Mp.: 168-170° C. (dec.). IR (KBr):3362br, m; 2956w; 1695s; 1596m; 1494m; 1447m; 1284s; 1243s; 1146s;1094s; 1018m; 937w; 883m; 810m; 736w; 700w; 666s. ¹H-NMR (300 MHz,CDCl₃): 2.39 (s, 3 H, ArCH₃); 4.00 (s, 3 H, OCH₃); 5.91 (bs, 1 H, OH);7.29 (d, J=7.8, 2 H, H_(arom, p-Tol.)); 7.55 (d, J=1.2, 1 H,H_(arom, Cat.)); 7.83 (d, J=7.8, 2 H, H_(arom, p-Tol.)); 8.05 (d, J=1.2,1 H, H_(arom, Cat.)); 11.43 (bs, 1 H, OH). ¹³C-NMR (75 MHz, CDCl₃):21.7; 53.1; 112.2; 117.8; 120.9; 127.4; 129.8; 132.8; 138.5; 144.1;145.6; 152.5; 169.6. HR-MS (MALDI): calcd. for C₁₅H14O₆SNa ([M+Na]⁺):345.0409, found 345.0402.

d) Methyl2,2-bis-(4-methoxy-phenyl)-6-(toluene-4-sulfonyl)-1,3-benzodioxole-4-carboxylate

4,4′-Dimethoxybenzophenone (225 mg, 0.93 mmol, 1.5 eq.), oxalyl chloride(944 mg, 7.44 mmol, 8 eq.) and methyl2,3-dihydroxy-5-(toluene-4-sulfonyl)-benzoate (200 mg, 0.62 mmol, 1 eq.)were reacted according to GP2.2. The crude product was purified usingflash chromatography (silica gel, hexane/EtOAc 20:1→9:1) to yield thetitle compound as a colorless solid.

Yield: 260 mg (77%). Mp.: 79-82° C. IR (KBr): 2951w; 2832w; 1727m;1610m; 1512m; 1464s; 1320m; 1285m; 1248s; 1210m; 1175s; 1150s; 1090m;1042m; 1004w; 885w; 832w; 739w; 663w; 616w. ¹H-NMR (300 MHz, CDCl₃):2.39 (s, 3 H, ArCH₃); 3.80 (s, 6 H, ArOCH₃); 3.93 (s, 3 H, C(O)OCH₃);6.88 (dt, J=8.7, 2.5, 4 H, H_(arom, Ketal)); 7.29 (d, J=8.1, 2 H,H_(arom, p-ToL)); 7.43 (m, 5 H, H_(arom, Cat.), H_(arom, Ketal);) 7.81(d, J=8.7, 2 H, H_(arom, p-Tol.)); 8.09 (d, J=1.8, 1 H, H_(arom, Cat.)).¹³C-NMR (75 MHz, CDCl₃): 21.7; 52.5; 55.4; 110.1; 112.5; 113.6; 120.9;124.0; 127.5; 127.9; 129.9; 130.7; 134.9; 138.4; 144.1; 149.2; 151.9;160.4; 163.4. HR-MS (MALDI): calcd. for C₃₀H₂₇O₈S ([M+H]⁺): 547.1427,found 547.1428. Anal. calcd. for C₃₀H₂₆O₈S: C 65.65, H 4.87. found C65.92, H 4.79.

e)2,2-Bis-(4-methoxy-phenyl)-6-(toluene-4-sulfonyl)-1,3-benzodioxole-4-carboxylicacid

Methyl2,2-bis-(4-methoxy-phenyl)-6-(toluene-4-sulfonyl)-1,3-benzodioxole-4-carboxylate(205 mg, 0.375 mmol, 1 eq.) and LiOH.H₂O (79 mg, 1.88 mmol, 5 eq.) werereacted following GP3.

Yield: 197 mg (99%). Colorless solid. IR (KBr): 3423br, w, 2961w; 2837w;1649w; 1611m; 1514m; 1443m; 1313s; 1254s; 1175s; 1119m; 1030s; 931w;903w; 832m; 675w. ¹H-NMR )300 MHz, CD₃OD): 2.32 (s, 3 H, ArCH₃); 3.73(s, 6 H, ArOCH₃); 6.85 (d, J=8.7, 4 H, H_(arom, Ketal)); 7.27 (d, J=8.1,2 H, H_(arom, p-Tol.)); 7.38 (d, J=8.7, 4 H, H_(arom, Ketal)); 7.43 (d,J=1.8, 1 H, H_(arom, Cat.)); 7.74 (d, J=8.1, 2 H, H_(arom, p-Tol.));8.03 (d, J=1.8, 1 H, H_(arom, Cat.)). ¹³C-NMR (75 MHz, CD₃OD): 21.5;55.8; 110.1; 114.0; 114.5; 125.4; 128.1; 128.4; 129.1; 130.8; 131.0;132.0; 133.2; 135.9; 139.1; 145.7; 150.5; 162.0. HR-MS (MALDI): calcd.for C₂₉H₂₅O₈S ([M+H]⁺): 533.1270, found 533.1274.

f)2,2-Bis-(4-methoxy-phenyl)-6-(toluene-4-sulfonyl)-benzo[1,3]dioxole-4-carboxylicacid{3-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-prop-2-enyl}-amide

2,2-Bis-(4-methoxy-phenyl)-6-(toluene-4-sulfonyl)-1,3-benzodioxole-4-carboxylicacid (160 mg, 0.3 mmol, 1 eq.), EDC.HCl (86 mg, 0.45 mmol, 1.5 eq.),N-hydroxy-succinimide (46 mg, 0.39 mmol, 1.3 eq.),9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydro-furo[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amine(100 mg, 0.31 mmol, 1 eq.) and Et₃N (0.1 mL, 0.68 mmol) were reactedaccording to GP7.

Yield: 146 mg (62%). Colorless foam. Mp.: 124-128° C. IR (KBr): 3424m;2930w; 1640s; 1638s; 1607s; 1514s; 1458s; 1374w; 1315m; 1249s; 1209m;1175s; 1184s; 1090s; 1004m; 833m; 664m; 616w. ¹H-NMR (300 MHz, CDCl₃):1.38 (s, 3 H, CH_(3-exo)); 1.61 (s, 3 H, CH_(3-endo)); 2.38 (s, 3 H,ArCH₃); 3.80 (s, 6 H, OCH₃); 4.01 (m, 2 H, H—C(7′), H—C(7″)); 4.69 (m, 1H, H—C(4′)); 4.94 (dd; J=6.5, 3.6, 1 H, H—C(3′)); 5.45 (dd, J=6.5, 2.1,1 H, H—C(2′)); 5.77 (m, 2 H, H—C(5′), H—C(6′)); 5.83 (bs, 2 H, NH₂);6.09 (d, J=2.1, 1 H, H—C(1′)); 6.88 (dt, J=8.7, 1.8, 4 H,H_(arom, Ketal)); 6.99 (t, J=5.7, 1 H, NHCO); 7.27 (d, J=7.8, 2 H,H_(arom, p-Tol.)); 7.31-7.38 (m, 4 H, H_(arom, Ketal)); 7.48 (d, J=1.8,1 H, H_(arom, Cat.)); 7.83 (d, J=7.8, 2 H, H_(arom, p-Tol.)); 7.84 (s, 1H, H—C(8)); 8.21 (s, 1 H, H—C(2)); 8.22 (d, J=1.8, 1 H, H_(arom, Cat.)).¹³C-NMR 75 MHz, CDCl₃): 21.7; 25.4; 27.2; 40.9; 55.4; 84.2; 84.5; 87.2;90.3; 109.8; 113.7; 114.5; 115.4; 120.1; 121.2; 124.0; 127.7; 128.1;128.5; 129.8; 130.2; 136.1; 138.2; 139.8; 144.1; 148.1; 148.3; 149.2;152.4; 155.0; 160.7; 161.6. HR-MS (MALDI): calcd. for C₄₄H₄₃N₆O₁₀S([M+H]⁺): 847.2761, found 847.2747. Anal. calcd. for C₄₄H₄₂N₆O₁₀S: C62.40, H 5.00, N 9.92. found C 62.16, H 5.21, N 9.81.

g)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(toluene-4-sulfonyl)-2,3-dihydroxy-benzamide

GP8, starting from the protected precursor (90 mg, 0.106 mmol) affordedthe desired product as a colorless solid.

Yield: 61 mg (98%). t_(R, analyt.): 13.9 min. IR (KBr): 3375br, s;1695s; 1639m; 1597m; 1548w; 1467w; 1430w; 1286m; 1201s; 1144s; 1098w;1051w; 973w; 799w; 723w; 666m. ¹H-NMR (500 MHz, CD₃OD): 2.37 (s, 3 H,CH₃); 4.05 (m, 2 H, H—C(7′), H—C(7″)); 4.23 (t, J=4.9, 1 H, H—C(4′));4.51 (t, J=4.9, 1 H, H—C(3′)); 4.72 (t, J=4.8, 1 H, H—C(2′)); 5.94 (m, 2H, H—C(5′), H—C(6′)); 6.05 (d, J=4.8, H—C(1′)); 7.33 (d, J=8.2,H_(arom, p-Tol.)); 7.35 (d, J=2.2, 1 H, H_(arom, Cat.)); 7.78 (d, J=8.2,H_(arom, p-Tol.)); 7.95 (d, J=2.2, 1 H, H_(arom, Cat.)); 8.25 (s, 1 H,H—C(8)); 8.38 (s, 1 H, H—C(2)). ¹³C-NMR (125 MHz, CD₃OD): 21.51; 41.8;75.3; 75.6; 86.1; 90.7; 117.0; 117.2; 119.5; 120.8; 128.5; 130.5; 130.8;131.1; 133.0; 140.5; 143.5; 145.7; 147.7; 148.6; 150.2; 153.5; 154.7;169.8. HR-MS (MALDI): calcd. for C₂₆H₂₇N₆O₆S ([M+H]⁺): 583.1611, found583.1600.

EXAMPLE 19 Preparation ofN1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]prop-2-enyl}-5-(4-methyl-benzoyl)-2,3-dihydroxy-benzamidea) (3-[1,3]Dioxan-2-yl-4,5-dimethoxy-phenyl)-p-tolyl-methanol

To a solution of 2-(5-Bromo-2,3-dimethoxy-phenyl)-[1,3]dioxane (2 g, 6.6mmol) in 13 mL dry THF cooled to −78° C., t-BuLi (1.5M solution inpentane, 2.5 eq.) was added dropwise via a syringe and the resultingdark red suspension was stirred 30 min. at −78° C. p-Tolualdehyde (1.2g, 10 mmol, 1.5 eq.) was added dropwise to the mixture and the resultingclear solution was stirred 30 min at −78° C., then 30 min at 0° C. H₂O(25 mL) was slowly added and the resulting solution was extracted withEtOAc (3×25 mL). The pooled organic fractions were dried over MgSO₄ andevaporated in vacuo. The crude product was purified using flashchromatography (silica gel, hexane/EtOAc 3:2) to yield the desiredcompound as a colorless solid.

(Takamitsu Hosoya, Eiji Takashiro, Takashi Matsumoto, Keisuke Suzuki, J.Am. Chem. Soc. 1994, 116, 1004-1015).

Yield: 2.13 g (94%). Mp.: 83-84° C. IR (KBr): 3464br, s; 2964m; 2851m;1596w; 1490s; 1380s; 1317s; 1241s; 1140s; 1079s; 999s; 896m; 824w; 772m.¹H-NMR (300 MHz, CDCl₃): 1.43 (bd, J=13.8, 1 H, CH₂); 2.23 (m, 1 H,CH₂); 2.32 (s, 3 H, Ar—CH₃); 3.80 (s, 3 H, OCH₃); 3.83 (s, 3 H, OCH₃);4.01 (tt, J=12.0, 2.7, 2 H, OCH₂); 4.24 (m, 2 H, OCH₂); 5.76 (bs, 1 H,O—CH(Ar)—O); 5.83 (s, 1 H, Ar—CH(OH)—Ar); 6.91 (d, J=1.8, 2 H,H_(arom)); 7.12 (d, J=8.1; 1 H, H_(arom, p-Tol.)); 7.25 (m, 3 H,H_(arom), H_(arom, p-Tol.)). ¹³C-NMR (75 MHz, CDCl₃): 21.2; 25.9; 55.9;61.4; 67.5; 75.9; 97.2; 110.8; 116.6; 126.4; 129.0; 132.1; 136.9; 140.1;140.5; 145.8; 152.4. HR-MS (MALDI): calcd. for C₂₀H₂₄O₅Na ([M+Na]⁺):367.1521, found 367.1513. Anal. calcd. for C₂₀H₂₄O₅: C 69.75, H 7.02.found C 69.81, H 7.15.

b) 2,3-Dimethoxy-5-(4-methyl-benzoyl)-benzoic acid

To a solution of(3-[1,3]Dioxan-2-yl-4,5-dimethoxy-phenyl)-p-tolyl-methanol (2.13 g, 6.18mmol) in 75 mL THF, 56 mL 8N H₂SO₄ was added and the resulting solutionwas stirred 2 h at 50° C. After addition of 50 mL saturatedNaCl-solution the mixture was extracted with EtOAc (3×50 mL). The pooledorganic fractions were washed with saturated NaHCO₃-solution (50 mL),then saturated NaCl-solution (50 mL) before being dried over MgSO₄ andevaporated under reduced pressure to yield the desired product as acolorless oil. This crude product (2 g) was added to a mixture of 45 mLt-BuOH, 24 mL of a 1.25M K₂HPO₄-solution and 37 mL of a IMKMnO₄-solution and stirred 45 min. at 60° C. The mixture was partitionedbetween 100 mL saturated NaCl-solution and 100 mL CHCl₃ and the aqueousphase was extracted with CHCl₃ (3×100 mL). The pooled organic fractionswere extracted with 2N NaOH-solution (3×100 mL), then the combinedaqueous fractions were acidified with conc. HCl and extracted with CHCl₃(4×100 mL). The organic fractions were pooled, dried over MgSO₄ andevaporated in vacuo to yield the title compound as a colorless solid.

Yield: 1.54 g (83%). Mp.: 135-136° C. IR (KBr): 2945br, s; 2620m; 1684s;1598s; 1487s; 1442s; 1405s; 1339s; 1277s; 1129s; 1069s; 995s; 909m;847m; 753s. ¹H-NMR (300 MHz, CDCl₃): 2.45 (s, 3 H, Ar—CH₃); 4.01 (s, 3H, OCH₃); 4.19 (s, 3 H, OCH₃); 7.30 (d, J=8.1, 2 H, H_(arom, p-Tol.));7.69 (d, J=8.1; 1 H, H_(arom, p-Tol.)); 7.72 (d, J=2.1; 1 H, H_(arom));8.06 (d, J=2.1; 1 H, H_(arom)) ¹³C-NMR (75 MHz, CDCl₃): 21.8; 56.4;62.4; 117.4; 121.7; 126.3; 129.1; 130.0; 133.9; 134.0; 143.6; 151.5;152.5; 165.6; 194.3. HR-MS (MALDI): calcd. for C₁₇H₁₇O₅ ([M+H]⁺):301.1076, found 301.1072.

c) 2,3-Dihydroxy-5-(4-methyl-benzoyl)-benzoic acid

2,3-Dimethoxy-5-(4-methyl-benzoyl)-benzoic acid (300 mg, 1 mmol) wastreated with a mixture of 6 mL 48% HBr and 3 mL AcOH and the mixture wasstirred 14 h at 140° C. After cooling to r.t., the product wasprecipitated by addition of H₂O (60 mL). The precipitate was collectedby filtration, washed with 60 mL H₂O and dried under reduced pressure.

Yield: 264 mg (97%). Mp.: 95-97° C. (dec.). IR (KBr): 3417br, s; 2566m;1680s; 1609s; 1566w; 1432s; 1295s; 1253s; 1179s; 1123m; 862m; 801m;753s. ¹H-NMR (300 MHz, CD₃OD): 2.44 (s, 3 H, Ar—CH₃); 7.33 (d, J=8.1,2H, H_(arom, p-Tol.)); 7.47 (d, J=2.2; 1 H, H_(arom)); 7.62 (d, J=8.1; 1H, H_(arom, p-Tol.)); 7.79 (d, J=2.2; 1 H, H_(arom)). ¹³C-NMR (75 MHz,CD₃OD): 21.6; 113.4; 121.5; 125.5; 129.4; 129.9; 130.7; 136.1; 144.3;147.2; 155.8; 173.1; 196.5. HR-MS (MALDI): calcd. for C₁₅H₁₁O₅ ([M+H]⁻):271.0607, found 271.0610.

d) 2,3-Dihydroxy-5-(4-methyl-benzoyl)-benzoic acid2,5-dioxo-pyrrolidin-1-yl ester

To a solution of 2,3-dihydroxy-5-(4-methyl-benzoyl)-benzoic acid (214mg, 0.79 mmol) in 10 mL dry THF cooled to 0° C., N-hydroxysuccinimide(136 mg, 1.18 mmol, 1.5 eq.) and N-cyclohexylcarbodiimide, N′-methylpolystyrene HL (Novabiochem) (1.9 eq./g, 832 mg, 2 eq.) were added andthe solution was stirred 14 h while the cooling bath slowly warmed up tor.t. The solution was filtered and the filtrate was evaporated underreduced pressure. The crude product was recrystallised from H₂O to yieldthe desired product as a brownish solid.

Yield: 233 mg (80%). Mp.: 93-95° C. (dec.). IR (KBr): 3341br, s; 2949m;1738s; 1653m; 1606m; 1482w; 1368m; 1323m; 1203s; 1068s; 914w; 755w;645w. ¹H-NMR (300 MHz, CD₃OD): 2.42 (s, 3 H, Ar—CH₃); 2.87 (s, 4 H,CH₂—CH₂); 7.33 (d, J=8.0, 2 H, H_(arom, p-Tol.)); 7.57 (d, J=1.7; 1 H,H_(arom)); 7.65 (d, J=8.0; 1 H, H_(arom, p-Tol.)); 7.87 (d, J=1.7; 1 H,H_(arom)). ¹³C-NMR (75 MHz, CD₃OD): 21.4; 26.4; 110.3; 121.9; 125.2;129.8; 130.0; 130.6; 135.7; 144.3; 147.6; 154.6; 163.6; 171.2; 195.6.HR-MS (MALDI): calcd. for C₁₉H₁₆NO₇ ([M+H]⁺): 370.0927, found 370.0918.

e)N1-{(E)-3-[(3aR,4R,6R,6aR)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-enyl}-5-(4-methyl-benzoyl)-2,3-dihydroxy-benzamide

To a solution of 2,3-dihydroxy-5-(4-methyl-benzoyl)-benzoic acid2,5-dioxo-pyrrolidin-1-yl ester (100 mg, 0.27 mmol) in DMF (4 mL),(2R,3S,4R,5R)-2-((E)-3-Amino-propenyl)-5-(6-amino-purin-9-yl)-tetrahydro-furan-3,4-diol(79 mg, 0.27 mmol, 1 eq.) and Et₃N (113 μL, 0.81 mmol, 3 eq.) were addedand the solution was stirred 18 h at r.t. The crude product was purifiedusing HPLC (RP C18, linear gradient of CH₃CN in H₂O with 0.1% TFA,5→100% in 20 min, flow of 1 mL/min (analytical), UV-detection at 254 nm)to yield the title compound as a colorless solid.

Yield: 54 mg (37%). t_(R, analyt.): 13.6 min. IR (KBr): 3378 br, s;1642s; 1604s; 1427m; 1296s; 1120m; 1043w; 753w. ¹H-NMR (500 MHz, CD₃OD):2.32 (s, 3 H, CH₃), 3.94 (m, 2 H, H—C(7′), H—C(7″)); 4.13 (t, J=5.0, 1H, H—C(4′)); 4.41 (m, 1 H, H—C(3′)); 4.63 (t, J=4.8, 1 H, H—C(2′)); 5.83(m, 2 H, H—C(5′), H—C(6′)); 5.95 (d, J=4.8, 1 H, H—C(1′)); 7.22 (d,J=8.2, 1 H, H_(arom, Cat., p-Tol.)); 7.28 (d, J=2, 1 H, H_(arom, Cat.));7.54 (d, J=8.2, 1 H, H_(arom, Cat., p-Tol.)); 7.70 (d, J=2, 1 H,H_(arom, Cat.)); 8.18 (s, 1 H, H—C(8)); 8.28 (s, 1 H, H—C(2)). ¹³C-NMR(125 MHz, (CD₃OD): 21.6; 41.6; 75.2; 75.6; 86.1; 90.6; 116.4; 120.3;120.7; 122.7; 129.7; 130.1; 130.3; 130.9; 131.1; 136.4; 143.3; 144.5;147.5; 148.0; 150.2; 153.6; 154.4; 170.4; 197.1. HR-MS (MALDI): calcd.for C₂₇H₂₇N₆O₇ ([M+H]⁺): 547.1941, found 547.1934.

Tablet Formulation (Wet Granulation) mg/tablet Item Ingredients 25 mg100 mg 1. Compound of formula I 25 100 2. Lactose Anhydrous DTG 105 303. Sta-Rx 1500 6 6 4. Microcrystalline Cellulose 30 30 5. MagnesiumStearate 1 1 Total 167 167Manufacturing Procedure

-   1. Mix items 1, 2, 3 and 4 and granulate with purified water.-   2. Dry the granules at 50° C.-   3. Pass the granules through suitable milling equipment.-   4. Add item 5 and mix for three minutes; compress on a suitable    press.

Capsule Formulation mg/capsule Item Ingredients 25 mg 100 mg 1. Compoundof formula I 25 100 2. Hydrous Lactose 123 148 3. Corn Starch 35 40 4.Talc 15 10 5. Magnesium Stearate 2 2 Total 200 300Manufacturing Procedure

-   1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.-   2. Add items 4 and 5 and mix for 3 minutes.-   3. Fill into a suitable capsule.

1. A compound of formula I

wherein R¹ is H, CN, halogen, —COR², —S(O)_(x)R², C₁₋₁₂-alkyl,C₂₋₁₂-alkenyl, C₃₋₈-cycloalkyl, a heterocyclyl group, an aryl group, aheteroaryl group, C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, aheterocyclyl-(C₁₋₃)-alkyl group, an aryl-(C₁₋₃)-alkyl group or aheteroaryl-(C₁₋₃)-alkyl group; wherein the alkyl, alkenyl, alkoxy,cycloalkyl, heterocyclyl group, aryl group and heteroaryl groups areoptionally substituted; R² is —N(R³)(R^(3′)), C₁₋₆-alkyl,C₃₋₈-cycloalkyl, heterocyclyl, aryl, heteroaryl,C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, a heterocyclyl-(C₁₋₃)-alkyl group, anaryl-(C₁₋₃)-alkyl group or a heteroaryl-(C₁₋₃)-alkyl group, wherein theC₁₋₆-alkyl, C₃₋₈-cycloalkyl, heterocyclyl, aryl, and heteroaryl areoptionally substituted; R³ and R^(3′) are independently hydrogen or(C₁₋₃)-alkyl; x is 0, 1 or 2; or an ester thereof which is hydrolyzableunder physiological conditions or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1, wherein R¹ is a hydrogen,cyano, halogen, —COR², —S(O)₂R², C₁₋₆-alkyl, C₁₋₆-alkyl substituted withhalogen, C₂₋₆-alkenyl substituted with COR², phenyl, phenyl substitutedwith C₁₋₆-alkyl or halogen, benzyl, or benzyl substituted withC₁₋₆-alkyl.
 3. A compound according to claim 2, wherein R² is C₁₋₆-alkylor C₁₋₆-alkyl substituted with halogen or —N(R³)(R^(3′)) and wherein R³and R^(3′) are each independently C₁₋₃-alkyl.
 4. A compound according toclaim 3, wherein R¹ is hydrogen, cyano, or halogen.
 5. A compoundaccording to claim 2, wherein R² is phenyl, phenyl substituted withC₁₋₆-alkyl or halogen, cyclohexyl, or heteroaryl.
 6. A compoundaccording to claim 5, wherein R¹ is hydrogen, cyano, or halogen.
 7. Acompound according to claim 5, wherein R² is pyridinyl, thiazolyl, orbenzthiazolyl.
 8. A compound according to claim 2, wherein heteroaryl ispyridinyl, thiazolyl, or benzthiazolyl.
 9. A compound according to claim3, wherein R¹ is hydrogen, cyano, or halogen.
 10. A compound accordingto claim 9, selected from the group consisting ofN-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-benzamide;N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-cyano-2,3-dihydroxy-benzamide;N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-bromo-2,3-dihydroxy-benzamide;andN-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-chloro-2,3-dihydroxy-benzamide.11. A compound according to claim 1, wherein R¹ is C₁₋₆-alkyl,C₁₋₆-alkyl substituted with halogen, or C₂₋₆-alkenyl substituted withCOR².
 12. A compound according to claim 11, wherein R² is —N(R³)(R^(3′))and wherein R³ and R^(3′) are each independently C₁₋₃-alkyl.
 13. Acompound according to claim 4, selected from the group consisting ofN-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl)-allyl}-2,3-dihydroxy-5-isopropyl-benzamide;N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-(2-dimethyl-carbamoyl-vinyl)-2,3-dihydroxy-benzamide;andN-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-trifluoromethyl-benzamide.14. A compound according to claim 1, wherein R¹ is —COR².
 15. A compoundaccording to claim 14, wherein R² is C₁₋₆-alkyl, C₁₋₆-alkyl substitutedwith halogen, or —N(R³)(R^(3′)) and wherein R³ and R^(3′) are eachindependently C₁₋₃-alkyl.
 16. A compound according to claim 15, selectedfrom the group consisting ofN-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-trifluoroacetyl-benzamide;andN3-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-4,5-dihydroxy-N1,N1-dimethyl-isophthalamide.17. A compound according to claim 14, wherein R² is phenyl, phenylsubstituted with C₁₋₆-alkyl or halogen, C₃₋₈-cycloalkyl, or heteroaryl.18. A compound according to claim 17, wherein R² is cyclohexyl.
 19. Acompound according to claim 17, wherein heteroaryl is pyridinyl,thiazolyl, or benzthiazolyl.
 20. A compound according to claim 17,selected from the group consisting ofN-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(4-methyl-benzoyl)-benzamide;N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-cyclohexanecarbonyl-2,3-dihydroxy-benzamide;andN-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(pyridine-4-carbonyl)-benzamide.21. A compound according to claim 1, wherein R¹ is —S(O)₂R².
 22. Acompound according to claim 21, wherein R² is C₁₋₆-alkyl, C₁₋₆-alkylsubstituted with halogen, or —N(R³)(R^(3′)) and wherein R³ and R^(3′)are each independently C₁₋₃-alkyl.
 23. A compound according to claim 21,wherein R² is phenyl, phenyl substituted with C₁₋₆-alkyl or halogen,cyclohexyl, or heteroaryl.
 24. A compound according to claim 23, whereinheteroaryl is pyridinyl, thiazolyl, or benzthiazolyl.
 25. A compoundaccording to claim 21, which is N-553-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(toluene-4-sulfonyl)-benzamide.26. A compound according to claim 1, wherein R¹ is phenyl, phenylsubstituted with C₁₋₆-alkyl or halogen, pyridinyl, thiazolyl,benzthiazolyl, benzyl, or benzyl substituted with C₁₋₆-alkyl.
 27. Acompound according to claim 26, selected from the group consisting of4′-Fluoro-4,5-dihydroxy-biphenyl-3-carboxylic acid{3-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-amide;N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-thiazol-2-yl-benzamide;N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-pyridin-4-yl-benzamide;4,5-Dihydroxy-4′-methyl-biphenyl-3-carboxylic acid{3-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-amide;N-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-5-benzothiazol-2-yl-2,3-dihydroxy-benzamide;andN-{3-[5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-allyl}-2,3-dihydroxy-5-(4-methyl-benzyl)-benzamide.28. A pharmaceutical composition comprising a therapeutically effectiveamount of one of more compounds of formula I

wherein R¹ is H, CN, halogen, —COR², —S(O)_(x)R², C₁₋₁₂-alkyl,C₂₋₁₂-alkenyl, C₃₋₈-cycloalkyl, a heterocyclyl group, an aryl group, aheteroaryl group, C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, aheterocyclyl-(C₁₋₃)-alkyl group, an aryl-(C₁₋₃)-alkyl group or aheteroaryl-(C₁₋₃)-alkyl group; wherein the alkyl, alkenyl, alkoxy,cycloalkyl, heterocyclyl group, aryl group and heteroaryl groups areoptionally substituted; R² is —N(R³)(R^(3′)), C₁₋₆-alkyl,C₃₋₈-cycloalkyl, heterocyclyl, aryl, heteroaryl,C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, a heterocyclyl-(C₁₋₃)-alkyl group, anaryl-(C₁₋₃)-alkyl group or a heteroaryl-(C₁₋₃)-alkyl group, wherein theC₁₋₆-alkyl, C₃₋₈-cycloalkyl, heterocyclyl, aryl, heteroaryl areoptionally substituted; R³ and R^(3′) are independently hydrogen or(C₁₋₃)-alkyl; x is 0, 1 or 2; or an ester thereof which is hydrolyzableunder physiological conditions or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.
 29. A method oftreating schizophreniza, comprising administering to an individual atherapeutically effective amount of a compound of formula I

wherein R¹ is H, CN, halogen, —COR², —S(O)_(x)R², C₁₋₁₂-alkyl,C₂₋₁₂-alkenyl, C₃₋₈-cycloalkyl, a heterocyclyl group, an aryl group, aheteroaryl group, C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, aheterocyclyl-(C₁₋₃)-alkyl group, an aryl-(C₁₋₃)-alkyl group or aheteroaryl-(C₁₋₃)-alkyl group; wherein the alkyl, alkenyl, alkoxy,cycloalkyl, heterocyclyl group, aryl group and heteroaryl groups areoptionally substituted; R² is —N(R³)(R^(3′)), C₁₋₆-alkyl,C₃₋₈-cycloalkyl, heterocyclyl, aryl, heteroaryl,C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, a heterocyclyl-(C₁₋₃)-alkyl group, anaryl-(C₁₋₃)-alkyl group or a heteroaryl-(C₁₋₃)-alkyl group, wherein theC₁₋₆-alkyl, C₃₋₈-cycloalkyl, heterocyclyl, aryl, heteroaryl areoptionally substituted; R³ and R^(3′) are independently hydrogen or(C₁₋₃)-alkyl; x is 0, 1 or 2; or an ester thereof which is hydrolyzableunder physiological conditions or a pharmaceutically acceptable saltthereof.
 30. A method of treating depression, comprising administeringto an individual a therapeutically effective amount of a compound offormula I

wherein R¹ is H, CN, halogen, —COR², —S(O)_(x)R², C₁₋₁₂-alkyl,C₂₋₁₂-alkenyl, C₃₋₈-cycloalkyl, a heterocyclyl group, an aryl group, aheteroaryl group, C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, aheterocyclyl-(C₁₋₃)-alkyl group, an aryl-(C₁₋₃)-alkyl group or aheteroaryl-(C₁₋₃)-alkyl group; wherein the alkyl, alkenyl, alkoxy,cycloalkyl, heterocyclyl group, aryl group and heteroaryl groups areoptionally substituted; R² is —N(R³)(R^(3′)), C₁₋₆-alkyl,C₃₋₈-cycloalkyl, heterocyclyl, aryl, heteroaryl,C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, a heterocyclyl-(C₁₋₃)-alkyl group, anaryl-(C₁₋₃)-alkyl group or a heteroaryl-(C₁₋₃)-alkyl group, wherein theC₁₋₆-alkyl, C₃₋₈-cycloalkyl, heterocyclyl, aryl, heteroaryl areoptionally substituted; R³ and R^(3′) are independently hydrogen or(C₁₋₃)-alkyl; x is 0, 1 or 2; or an ester thereof which is hydrolyzableunder physiological conditions or a pharmaceutically acceptable saltthereof.
 31. A process for preparing a compound of formula I

wherein R¹ is H, CN, halogen, —COR², —S(O)_(x)R², C₁₋₁₂-alkyl,C₂₋₁₂-alkenyl, C₃₋₈-cycloalkyl, a heterocyclyl group, an aryl group, aheteroaryl group, C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, aheterocyclyl-(C₁₋₃)-alkyl group, an aryl-(C₁₋₃)-alkyl group or aheteroaryl-(C₁₋₃)-alkyl group; wherein the alkyl, alkenyl, alkoxy,cycloalkyl, heterocyclyl group, aryl group and heteroaryl groups areoptionally substituted; R² is —N(R³)(R^(3′)), C₁₋₆-alkyl,C₃₋₈-cycloalkyl, heterocyclyl, aryl, heteroaryl,C₃₋₈-cycloalkyl-(C₁₋₃)-alkyl, a heterocyclyl-(C₁₋₃)-alkyl group, anaryl-(C₁₋₃)-alkyl group or a heteroaryl-(C₁₋₃)-alkyl group, wherein theC₁₋₆-alkyl, C₃₋₈-cycloalkyl, heterocyclyl, aryl, heteroaryl areoptionally substituted; R³ and R^(3′) are independently hydrogen or(C₁₋₃)-alkyl; x is 0, 1 or 2; said process comprising a) reacting9-{(3aR,4R,6R,6aR)-6-[(E)-3-aminoprop-1-enyl]-2,2-dimethylperhydro-furo[3,4-d][1,3]di-oxol-4-yl}-9H-purin-6-amineof formula II

with an optionally protected 2,3-dihydroxy-benzoic acid derivative offormula IIIa or IIIb substituted by R¹ in position 5

wherein R¹ is as defined above in the presence of(3-dimethylamino-propyl)-ethyl-carbodiimide (EDC), triethyl amine andN-hydroxy-succinimide (HOSu) in a solvent; and b) optionallydeprotecting the hydroxy groups with trifluoroacetic acid in an aqueoussolution to form a compound of formula I.